bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023‒12‒03
sixteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. FOXP1 and KLF2 reciprocally regulate checkpoints of stem-like to effector transition in CAR T cells.
  2. Metabolic influences on T cell in psoriasis: a literature review.
  3. Immunosenescence and cancer: Opportunities and challenges.
  4. Mettl3-dependent m6A modification is essential for effector differentiation and memory formation of CD8+ T cells.
  5. PA suppresses antitumor immunity of T cells by disturbing mitochondrial activity through Akt/mTOR-mediated Ca2+ flux.
  6. Impact of NAD+ metabolism on ovarian aging.
  7. IGF2 deficiency promotes liver aging through mitochondrial dysfunction and upregulated CEBPB signaling in D-galactose-induced aging mice.
  8. The immunometabolic ecosystem in cancer.
  9. Enhancing CAR-T Cell Metabolism to Overcome Hypoxic Conditions in the Brain Tumor Microenvironment.
  10. Metabolic control of mitophagy.
  11. Intestinal microbiota-specific Th17 cells possess regulatory properties and suppress effector T cells via c-MAF and IL-10.
  12. Protective Effects of Apigenin on the Brain Transcriptome with Aging.
  13. Activation of the aryl hydrocarbon receptor inhibits neuropilin-1 upregulation on IL-2-responding CD4+ T cells.
  14. Metabolic Rewiring and Communication: An Integrative View of Kidney Proximal Tubule Function.
  15. PD-1 Impairs CD8+ T Cell Granzyme B Production in Aged Mice during Acute Viral Respiratory Infection.
  16. Mitophagy in human health, ageing and disease.
  1. Nat Immunol. 2023 Nov 27.
    FOXP1 and KLF2 reciprocally regulate checkpoints of stem-like to effector transition in CAR T cells.
    Ziang Zhu, Guohua Lou, Xiao-Lu Teng, Haixia Wang, Ying Luo, Wangke Shi, Kiddist Yihunie, Shumeng Hao, Kole DeGolier, Chengheng Liao, Huocong Huang, Qing Zhang, Terry Fry, Tao Wang, Chen Yao, Tuoqi Wu.
      In cancer and infections, self-renewing stem-like CD8+ T cells mediate the response of immunotherapies and replenish terminally exhausted T cells and effector-like T cells. However, the programs governing the lineage choice in chimeric antigen receptor (CAR) T cells are unclear. Here, by simultaneously profiling single-cell chromatin accessibility and transcriptome in the same CAR T cells, we identified heterogeneous chromatin states within CD8+ T cell subsets that foreshadowed transcriptional changes and were primed for regulation by distinct transcription factors. Transcription factors that controlled each CD8+ T cell subset were regulated by high numbers of enhancers and positioned as hubs of gene networks. FOXP1, a hub in the stem-like network, promoted expansion and stemness of CAR T cells and limited excessive effector differentiation. In the effector network, KLF2 enhanced effector CD8+ T cell differentiation and prevented terminal exhaustion. Thus, we identified gene networks and hub transcription factors that controlled the differentiation of stem-like CD8+ CAR T cells into effector or exhausted CD8+ CAR T cells.
    DOI:  https://doi.org/10.1038/s41590-023-01685-w
  2. Front Immunol. 2023 ;14 1279846
    Metabolic influences on T cell in psoriasis: a literature review.
    Rina Su, Siqi Zhao, Jinqing Zhang, Mei Cao, Shiguang Peng.
      Psoriasis is a systemic inflammatory disease that frequently coexists with various other conditions, such as essential hypertension, diabetes, metabolic syndrome, and inflammatory bowel disease. The association between these diseases may be attributed to shared inflammatory pathways and abnormal immunomodulatory mechanisms. Furthermore, metabolites also play a regulatory role in the function of different immune cells involved in psoriasis pathogenesis, particularly T lymphocytes. In this review, we have summarized the current research progress on T cell metabolism in psoriasis, encompassing the regulation of metabolites in glucose metabolism, lipid metabolism, amino acid metabolism, and other pathways within T cells affected by psoriasis. We will also explore the interaction and mechanism between psoriatic metabolites and immune cells. Moreover, we further discussed the research progress of metabolomics in psoriasis to gain a deeper understanding of its pathogenesis and identify potential new therapeutic targets through identification of metabolic biomarkers associated with this condition.
    Keywords:  T cell; amino acid metabolism; glucose metabolism; lipid metabolism; psoriasis
    DOI:  https://doi.org/10.3389/fimmu.2023.1279846
  3. Medicine (Baltimore). 2023 Nov 24. 102(47): e36045
    Immunosenescence and cancer: Opportunities and challenges.
    Zhibin Fu, Hailong Xu, Lanping Yue, Weiwei Zheng, Linkang Pan, Fangyi Gao, Xingshan Liu.
      As individuals age, cancer becomes increasingly common. This continually rising risk can be attributed to various interconnected factors that influence the body's susceptibility to cancer. Among these factors, the accumulation of senescent cells in tissues and the subsequent decline in immune cell function and proliferative potential are collectively referred to as immunosenescence. Reduced T-cell production, changes in secretory phenotypes, increased glycolysis, and the generation of reactive oxygen species are characteristics of immunosenescence that contribute to cancer susceptibility. In the tumor microenvironment, senescent immune cells may promote the growth and spread of tumors through multiple pathways, thereby affecting the effectiveness of immunotherapy. In recent years, immunosenescence has gained increasing attention due to its critical role in tumor development. However, our understanding of how immunosenescence specifically impacts cancer immunotherapy remains limited, primarily due to the underrepresentation of elderly patients in clinical trials. Furthermore, there are several age-related intervention methods, including metformin and rapamycin, which involve genetic and pharmaceutical approaches. This article aims to elucidate the defining characteristics of immunosenescence and its impact on malignant tumors and immunotherapy. We particularly focus on the future directions of cancer treatment, exploring the complex interplay between immunosenescence, cancer, and potential interventions.
    DOI:  https://doi.org/10.1097/MD.0000000000036045
  4. Sci Bull (Beijing). 2023 Nov 16. pii: S2095-9273(23)00797-1. [Epub ahead of print]
    Mettl3-dependent m6A modification is essential for effector differentiation and memory formation of CD8+ T cells.
    Wenhui Guo, Zhao Wang, Yajiao Zhang, Yashu Li, Qian Du, Tiantian Zhang, Jin Hu, Yingpeng Yao, Jiarui Zhang, Yingdi Xu, Xiao Cui, Zhen Sun, Menghao You, Guotao Yu, Haojian Zhang, Xuguang Du, Jingyu Xu, Shuyang Yu.
      Efficient immune responses rely on the proper differentiation of CD8+ T cells into effector and memory cells. Here, we show a critical requirement of N6-Methyladenosine (m6A) methyltransferase Mettl3 during CD8+ T cell responses upon acute viral infection. Conditional deletion of Mettl3 in CD8+ T cells impairs effector expansion and terminal differentiation in an m6A-dependent manner, subsequently affecting memory formation and the secondary response of CD8+ T cells. Our combined RNA-seq and m6A-miCLIP-seq analyses reveal that Mettl3 deficiency broadly impacts the expression of cell cycle and transcriptional regulators. Remarkably, Mettl3 binds to the Tbx21 transcript and stabilizes it, promoting effector differentiation of CD8+ T cells. Moreover, ectopic expression of T-bet partially restores the defects in CD8+ T cell differentiation in the absence of Mettl3. Thus, our study highlights the role of Mettl3 in regulating multiple target genes in an m6A-dependent manner and underscores the importance of m6A modification during CD8+ T cell response.
    Keywords:  CD8(+) T cell; Effector; Memory; Mettl3; T cell response; m(6)A
    DOI:  https://doi.org/10.1016/j.scib.2023.11.029
  5. Cancer Lett. 2023 Nov 25. pii: S0304-3835(23)00462-7. [Epub ahead of print]581 216511
    PA suppresses antitumor immunity of T cells by disturbing mitochondrial activity through Akt/mTOR-mediated Ca2+ flux.
    Shishuo Sun, Heng Xu, Wanxin Zhao, Qihong Li, Yifan Yuan, Guopeng Zhang, Shuyu Li, Bixi Wang, Wei Zhang, Xiaoge Gao, Junnian Zheng, Qing Zhang.
      Deciphering the mechanisms behind how T cells become exhausted and regulatory T cells (Tregs) differentiate in a tumor microenvironment (TME) will significantly benefit cancer immunotherapy. A common metabolic alteration feature in TME is lipid accumulation, associated with T cell exhaustion and Treg differentiation. However, the regulatory role of free fatty acids (FFA) on T cell antitumor immunity has yet to be clearly illustrated. Our study observed that palmitic acid (PA), the most abundant saturated FFA in mouse plasma, enhanced T cell exhaustion and Tregs population in TME and increased tumor growth. In contrast, oleic acid (OA), a monounsaturated FFA, rescued PA-induced T cell exhaustion, decreased Treg population, and ameliorated T cell antitumor immunity in an obese mouse model. Mechanistically, mitochondrial metabolic activity is critical in maintaining T cell function, which PA attenuated. PA-induced T cell exhaustion and Treg formation depended on CD36 and Akt/mTOR-mediated calcium signaling. The study described a new mechanism of PA-induced downregulation of antitumor immunity of T cells and the therapeutic potential behind its restoration by targeting PA.
    Keywords:  Antitumor immunity; OA; PA; T cells; TME
    DOI:  https://doi.org/10.1016/j.canlet.2023.216511
  6. Immun Ageing. 2023 Dec 02. 20(1): 70
    Impact of NAD+ metabolism on ovarian aging.
    Jinghui Liang, Feiling Huang, Zhaoqi Song, Ruiyi Tang, Peng Zhang, Rong Chen.
      Nicotinamide adenine dinucleotide (NAD+), a crucial coenzyme in cellular redox reactions, is closely associated with age-related functional degeneration and metabolic diseases. NAD exerts direct and indirect influences on many crucial cellular functions, including metabolic pathways, DNA repair, chromatin remodeling, cellular senescence, and immune cell functionality. These cellular processes and functions are essential for maintaining tissue and metabolic homeostasis, as well as healthy aging. Causality has been elucidated between a decline in NAD levels and multiple age-related diseases, which has been confirmed by various strategies aimed at increasing NAD levels in the preclinical setting. Ovarian aging is recognized as a natural process characterized by a decline in follicle number and function, resulting in decreased estrogen production and menopause. In this regard, it is necessary to address the many factors involved in this complicated procedure, which could improve fertility in women of advanced maternal age. Concerning the decrease in NAD+ levels as ovarian aging progresses, promising and exciting results are presented for strategies using NAD+ precursors to promote NAD+ biosynthesis, which could substantially improve oocyte quality and alleviate ovarian aging. Hence, to acquire further insights into NAD+ metabolism and biology, this review aims to probe the factors affecting ovarian aging, the characteristics of NAD+ precursors, and the current research status of NAD+ supplementation in ovarian aging. Specifically, by gaining a comprehensive understanding of these aspects, we are optimistic about the prominent progress that will be made in both research and therapy related to ovarian aging.
    Keywords:  Infertility; Metabolic homeostasis; NAD+ metabolism; Ovary aging
    DOI:  https://doi.org/10.1186/s12979-023-00398-w
  7. Mol Med. 2023 Nov 28. 29(1): 161
    IGF2 deficiency promotes liver aging through mitochondrial dysfunction and upregulated CEBPB signaling in D-galactose-induced aging mice.
    Xiaohai Zhou, Bowen Tan, Weiwei Gui, Caiping Zhou, Hanxin Zhao, Xihua Lin, Hong Li.
      BACKGROUND: Liver aging, marked by cellular senescence and low-grade inflammation, heightens susceptibility to chronic liver disease and worsens its prognosis. Insulin-like growth factor 2 (IGF2) has been implicated in numerous aging-related diseases. Nevertheless, its role and underlying molecular mechanisms in liver aging remain largely unexplored.METHODS: The expression of IGF2 was examined in the liver of young (2-4 months), middle-aged (9-12 months), and old (24-26 months) C57BL/6 mice. In vivo, we used transgenic IGF2f/f; Alb-Cre mice and D-galactose-induced aging model to explore the role of IGF2 in liver aging. In vitro, we used specific short hairpin RNA against IGF2 to knock down IGF2 in AML12 cells. D-galactose and hydrogen peroxide treatment were used to induce AML12 cell senescence.
    RESULTS: We observed a significant reduction of IGF2 levels in the livers of aged mice. Subsequently, we demonstrated that IGF2 deficiency promoted senescence phenotypes and senescence-associated secretory phenotypes (SASPs), both in vitro and in vivo aging models. Moreover, IGF2 deficiency impaired mitochondrial function, reducing mitochondrial respiratory capacity, mitochondrial membrane potential, and nicotinamide adenine dinucleotide (NAD)+/NADH ratio, increasing intracellular and mitochondrial reactive oxygen species levels, and disrupting mitochondrial membrane structure. Additionally, IGF2 deficiency markedly upregulated CCAAT/enhancer-binding protein beta (CEBPB). Notably, inhibiting CEBPB reversed the senescence phenotypes and reduced SASPs induced by IGF2 deficiency.
    CONCLUSIONS: In summary, our findings strongly suggest that IGF2 deficiency promotes liver aging through mitochondrial dysfunction and upregulated CEBPB signaling. These results provide compelling evidence for considering IGF2 as a potential target for interventions aimed at slowing down the process of liver aging.
    Keywords:  Aging; CEBPB; IGF2; Liver; Mitochondria dysfunction
    DOI:  https://doi.org/10.1186/s10020-023-00752-0
  8. Nat Immunol. 2023 Dec;24(12): 2008-2020
    The immunometabolic ecosystem in cancer.
    Glenn R Bantug, Christoph Hess.
      Our increased understanding of how key metabolic pathways are activated and regulated in malignant cells has identified metabolic vulnerabilities of cancers. Translating this insight to the clinics, however, has proved challenging. Roadblocks limiting efficacy of drugs targeting cancer metabolism may lie in the nature of the metabolic ecosystem of tumors. The exchange of metabolites and growth factors between cancer cells and nonmalignant tumor-resident cells is essential for tumor growth and evolution, as well as the development of an immunosuppressive microenvironment. In this Review, we will examine the metabolic interplay between tumor-resident cells and how targeted inhibition of specific metabolic enzymes in malignant cells could elicit pro-tumorigenic effects in non-transformed tumor-resident cells and inhibit the function of tumor-specific T cells. To improve the efficacy of metabolism-targeted anticancer strategies, a holistic approach that considers the effect of metabolic inhibitors on major tumor-resident cell populations is needed.
    DOI:  https://doi.org/10.1038/s41590-023-01675-y
  9. bioRxiv. 2023 Nov 15. pii: 2023.11.13.566775. [Epub ahead of print]
    Enhancing CAR-T Cell Metabolism to Overcome Hypoxic Conditions in the Brain Tumor Microenvironment.
    Ryusuke Hatae, Keith Kyewalabye, Akane Yamamichi, Tiffany Chen, Su Phyu, Pavlina Chuntova, Takahide Nejo, Lauren S Levine, Matthew H Spitzer, Hideho Okada.
      The efficacy of chimeric antigen receptor (CAR)-T therapy has been limited against brain tumors to date. CAR-T cells infiltrating syngeneic intracerebral SB28-EGFRvIII glioma revealed impaired mitochondrial ATP production and a markedly hypoxic status compared to ones migrating to subcutaneous tumors. Drug screenings to improve metabolic states of T cells under hypoxic conditions led us to evaluate the combination of AMPK activator Metformin and the mTOR inhibitor Rapamycin (Met+Rap). Met+Rap-pretreated mouse CAR-T cells showed activated PPAR-gamma coactivator 1α (PGC-1α) through mTOR inhibition and AMPK activation, and a higher level of mitochondrial spare respiratory capacity than those pretreated with individual drugs or without pretreatment. Moreover, Met+Rap-pretreated CAR-T cells demonstrated persistent and effective anti-glioma cytotoxic activities in the hypoxic condition. Furthermore, a single intravenous infusion of Met+Rap-pretreated CAR-T cells significantly extended the survival of mice bearing intracerebral SB28-EGFRvIII gliomas. Mass cytometric analyses highlighted increased glioma-infiltrating CAR-T cells in the Met+Rap group with fewer Ly6c+ CD11b+ monocytic myeloid-derived suppressor cells in the tumors. Finally, human CAR-T cells pretreated with Met+Rap recapitulated the observations with murine CAR-T cells, demonstrating improved functions in vitro hypoxic conditions. These findings advocate for translational and clinical exploration of Met+Rap-pretreated CAR-T cells in human trials.
    DOI:  https://doi.org/10.1101/2023.11.13.566775
  10. Eur J Clin Invest. 2023 Dec 01. e14138
    Metabolic control of mitophagy.
    Andreas Zimmermann, Frank Madeo, Abhinav Diwan, Junichi Sadoshima, Simon Sedej, Guido Kroemer, Mahmoud Abdellatif.
      Mitochondrial dysfunction is a major hallmark of ageing and related chronic disorders. Controlled removal of damaged mitochondria by the autophagic machinery, a process known as mitophagy, is vital for mitochondrial homeostasis and cell survival. The central role of mitochondria in cellular metabolism places mitochondrial removal at the interface of key metabolic pathways affecting the biosynthesis or catabolism of acetyl-coenzyme A, nicotinamide adenine dinucleotide, polyamines, as well as fatty acids and amino acids. Molecular switches that integrate the metabolic status of the cell, like AMP-dependent protein kinase, protein kinase A, mechanistic target of rapamycin and sirtuins, have also emerged as important regulators of mitophagy. In this review, we discuss how metabolic regulation intersects with mitophagy. We place special emphasis on the metabolic regulatory circuits that may be therapeutically targeted to delay ageing and mitochondria-associated chronic diseases. Moreover, we identify outstanding knowledge gaps, such as the ill-defined distinction between basal and damage-induced mitophagy, which must be resolved to boost progress in this area.
    Keywords:  AMPK; NAD; acetyl-CoA; ageing; ageing-related disease; metabolism; mitophagy; spermidine
    DOI:  https://doi.org/10.1111/eci.14138
  11. Immunity. 2023 Nov 29. pii: S1074-7613(23)00484-3. [Epub ahead of print]
    Intestinal microbiota-specific Th17 cells possess regulatory properties and suppress effector T cells via c-MAF and IL-10.
    Leonie Brockmann, Alexander Tran, Yiming Huang, Madeline Edwards, Carlotta Ronda, Harris H Wang, Ivaylo I Ivanov.
      Commensal microbes induce cytokine-producing effector tissue-resident CD4+ T cells, but the function of these T cells in mucosal homeostasis is not well understood. Here, we report that commensal-specific intestinal Th17 cells possess an anti-inflammatory phenotype marked by expression of interleukin (IL)-10 and co-inhibitory receptors. The anti-inflammatory phenotype of gut-resident commensal-specific Th17 cells was driven by the transcription factor c-MAF. IL-10-producing commensal-specific Th17 cells were heterogeneous and derived from a TCF1+ gut-resident progenitor Th17 cell population. Th17 cells acquired IL-10 expression and anti-inflammatory phenotype in the small-intestinal lamina propria. IL-10 production by CD4+ T cells and IL-10 signaling in intestinal macrophages drove IL-10 expression by commensal-specific Th17 cells. Intestinal commensal-specific Th17 cells possessed immunoregulatory functions and curbed effector T cell activity in vitro and in vivo in an IL-10-dependent and c-MAF-dependent manner. Our results suggest that tissue-resident commensal-specific Th17 cells perform regulatory functions in mucosal homeostasis.
    Keywords:  IL-10; TCF1; Th17 cells; Treg; c-MAF; commensal-specific CD4 T cells; intestine; microbiota; mucosal immunology; segmented filamentous bacteria
    DOI:  https://doi.org/10.1016/j.immuni.2023.11.003
  12. Mech Ageing Dev. 2023 Nov 23. pii: S0047-6374(23)00115-X. [Epub ahead of print] 111889
    Protective Effects of Apigenin on the Brain Transcriptome with Aging.
    Alyssa N Cavalier, Zachary S Clayton, Devin Wahl, David A Hutton, Cali M McEntee, Douglas R Seals, Thomas J LaRocca.
      Brain aging is associated with reduced cognitive function that increases the risk for dementia. Apigenin is a bioactive plant compound that inhibits cellular aging processes and could protect against age-related cognitive dysfunction, but its mechanisms of action in the brain have not been comprehensively studied. We characterized brain transcriptome changes in young and old mice treated with apigenin in drinking water. We observed improved learning/memory in old treated mice, and our transcriptome analyses indicated that differentially expressed genes with aging and apigenin were primarily related to immune responses, inflammation, and cytokine regulation. Moreover, we found that genes/transcripts that were increased in old vs. young mice but downregulated with apigenin treatment in old animals were associated with immune activation/inflammation, whereas transcripts that were reduced with aging but increased with apigenin were related neuronal function and signaling. We also found that these transcriptome differences with aging and apigenin treatment were driven in part by glial cells. To follow up on these in vivo transcriptome findings, we studied aged astrocytes in vitro, and we found that apigenin reduced markers of inflammation and cellular senescence in these cells. Collectively, our data suggest that apigenin may protect against age-related cognitive dysfunction by suppressing neuro-inflammatory processes.
    Keywords:  Astrocytes; Cognitive decline; brain aging; neuroinflammation; transcriptomics
    DOI:  https://doi.org/10.1016/j.mad.2023.111889
  13. Front Immunol. 2023 ;14 1193535
    Activation of the aryl hydrocarbon receptor inhibits neuropilin-1 upregulation on IL-2-responding CD4+ T cells.
    Simone Sandoval, Keegan Malany, Krista Thongphanh, Clarisa A Martinez, Michael L Goodson, Felipe Da Costa Souza, Lo-Wei Lin, Nicolle Sweeney, Jamie Pennington, Pamela J Lein, Nancy I Kerkvliet, Allison K Ehrlich.
      Neuropilin-1 (Nrp1), a transmembrane protein expressed on CD4+ T cells, is mostly studied in the context of regulatory T cell (Treg) function. More recently, there is increasing evidence that Nrp1 is also highly expressed on activated effector T cells and that increases in these Nrp1-expressing CD4+ T cells correspond with immunopathology across several T cell-dependent disease models. Thus, Nrp1 may be implicated in the identification and function of immunopathologic T cells. Nrp1 downregulation in CD4+ T cells is one of the strongest transcriptional changes in response to immunoregulatory compounds that act though the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor. To better understand the link between AhR and Nrp1 expression on CD4+ T cells, Nrp1 expression was assessed in vivo and in vitro following AhR ligand treatment. In the current study, we identified that the percentage of Nrp1 expressing CD4+ T cells increases over the course of activation and proliferation in vivo. The actively dividing Nrp1+Foxp3- cells express the classic effector phenotype of CD44hiCD45RBlo, and the increase in Nrp1+Foxp3- cells is prevented by AhR activation. In contrast, Nrp1 expression is not modulated by AhR activation in non-proliferating CD4+ T cells. The downregulation of Nrp1 on CD4+ T cells was recapitulated in vitro in cells isolated from C57BL/6 and NOD (non-obese diabetic) mice. CD4+Foxp3- cells expressing CD25, stimulated with IL-2, or differentiated into Th1 cells, were particularly sensitive to AhR-mediated inhibition of Nrp1 upregulation. IL-2 was necessary for AhR-dependent downregulation of Nrp1 expression both in vitro and in vivo. Collectively, the data demonstrate that Nrp1 is a CD4+ T cell activation marker and that regulation of Nrp1 could be a previously undescribed mechanism by which AhR ligands modulate effector CD4+ T cell responses.
    Keywords:  CD4+ T cells; IL-2; aryl hydrocarbon receptor; immunomodulators; neuropilin-1
    DOI:  https://doi.org/10.3389/fimmu.2023.1193535
  14. Annu Rev Physiol. 2023 Nov 27.
    Metabolic Rewiring and Communication: An Integrative View of Kidney Proximal Tubule Function.
    Maria Chrysopoulou, Markus M Rinschen.
      The kidney proximal tubule is a key organ for human metabolism. The kidney responds to stress with altered metabolite transformation and perturbed metabolic pathways, an ultimate cause for kidney disease. Here, we review the proximal tubule's metabolic function through an integrative view of transport, metabolism, and function, and embed it in the context of metabolome-wide data-driven research. Function (filtration, transport, secretion, and reabsorption), metabolite transformation, and metabolite signaling determine kidney metabolic rewiring in disease. Energy metabolism and substrates for key metabolic pathways are orchestrated by metabolite sensors. Given the importance of renal function for the inner milieu, we also review metabolic communication routes with other organs. Exciting research opportunities exist to understand metabolic perturbation of kidney and proximal tubule function, for example, in hypertension-associated kidney disease. We argue that, based on the integrative view outlined here, kidney diseases without genetic cause should be approached scientifically as metabolic diseases. Expected final online publication date for the Annual Review of Physiology, Volume 86 is February 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-physiol-042222-024724
  15. Immunohorizons. 2023 Nov 01. 7(11): 771-787
    PD-1 Impairs CD8+ T Cell Granzyme B Production in Aged Mice during Acute Viral Respiratory Infection.
    Olivia B Parks, Danielle Antos, Taylor Eddens, Sara Walters, Monika Johnson, Tim D Oury, Rachel A Gottschalk, John J Erickson, John V Williams.
      CD8+ T cell dysfunction contributes to severe respiratory viral infection outcomes in older adults. CD8+ T cells are the primary cell type responsible for viral clearance. With increasing age, CD8+ T cell function declines in conjunction with an accumulation of cytotoxic tissue-resident memory (TRM) CD8+ T cells. We sought to elucidate the role of PD-1 signaling on aged CD8+ T cell function and accumulation of CD8+ TRM cells during acute viral respiratory tract infection, given the importance of PD-1 regulating CD8+ T cells during acute and chronic infections. PD-1 blockade or genetic ablation in aged mice yielded improved CD8+ T cell granzyme B production comparable to that in young mice during human metapneumovirus and influenza viral infections. Syngeneic transplant and adoptive transfer strategies revealed that improved granzyme B production in aged Pdcd1-/- CD8+ T cells was primarily cell intrinsic because aged wild-type CD8+ T cells did not have increased granzyme B production when transplanted into a young host. PD-1 signaling promoted accumulation of cytotoxic CD8+ TRM cells in aged mice. PD-1 blockade of aged mice during rechallenge infection resulted in improved clinical outcomes that paralleled reduced accumulation of CD8+ TRM cells. These findings suggest that PD-1 signaling impaired CD8+ T cell granzyme B production and contributed to CD8+ TRM cell accumulation in the aged lung. These findings have implications for future research investigating PD-1 checkpoint inhibitors as a potential therapeutic option for elderly patients with severe respiratory viral infections.
    DOI:  https://doi.org/10.4049/immunohorizons.2300094
  16. Nat Metab. 2023 Nov 30.
    Mitophagy in human health, ageing and disease.
    Anna Picca, Julie Faitg, Johan Auwerx, Luigi Ferrucci, Davide D'Amico.
      Maintaining optimal mitochondrial function is a feature of health. Mitophagy removes and recycles damaged mitochondria and regulates the biogenesis of new, fully functional ones preserving healthy mitochondrial functions and activities. Preclinical and clinical studies have shown that impaired mitophagy negatively affects cellular health and contributes to age-related chronic diseases. Strategies to boost mitophagy have been successfully tested in model organisms, and, recently, some have been translated into clinics. In this Review, we describe the basic mechanisms of mitophagy and how mitophagy can be assessed in human blood, the immune system and tissues, including muscle, brain and liver. We outline mitophagy's role in specific diseases and describe mitophagy-activating approaches successfully tested in humans, including exercise and nutritional and pharmacological interventions. We describe how mitophagy is connected to other features of ageing through general mechanisms such as inflammation and oxidative stress and forecast how strengthening research on mitophagy and mitophagy interventions may strongly support human health.
    DOI:  https://doi.org/10.1038/s42255-023-00930-8
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