bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–03–30
twenty-two papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research



  1. Aging Dis. 2025 Mar 15.
      The aging immune system presents profound challenges, notably through the decline of T cell function, which is critical for effective immune responses. As age-related changes lead to diminished T cell diversity and heighten immunosuppressive environments, older individuals face increased susceptibility to infections, autoimmune diseases, and reduced efficacy of immunotherapies. This review investigates the intricate mechanisms by which T cell aging drives immunosenescence, including immune suppression, immune evasion, reduced antigen reactivity, and the overexpression of immune checkpoint molecules. By delving into innovative therapeutic strategies aimed at rejuvenating T cell populations and modifying the immunological landscape, we highlight the potential for enhancing immune resilience in the elderly. Ultimately, our goal is to outline actionable pathways for restoring immune function, thereby improving health outcomes for aging individuals facing immunological decline.
    DOI:  https://doi.org/10.14336/AD.2025.0061
  2. Cancer Sci. 2025 Mar 25.
      Tumor-specific CD8+ T cells play a pivotal role in anti-tumor immunity. Here, we review the heterogeneity of CD8+ T cell subsets during tumor progression. While both acute and chronic viral infections induce distinct CD8+ T cell responses, chronic responses are also observed during tumor development. Chronic immune responses have traditionally been considered to represent a dysfunctional state of CD8+ T cells, whereas the identification of TCF1+ stem-like CD8+ T cells has highlighted their importance in anti-tumor immunity. During tumor progression, TCF1+ stem-like CD8+ T cells differentiate into cytotoxic Tim-3+ terminally differentiated CD8+ T cells through mechanisms that remain largely unknown. We recently identified CD69 as an important regulator of chronic CD8+ T cell responses and showed that blocking CD69 function, either through the administration of anti-CD69 antibody (Ab) or genetic knockout, enhanced the generation of cytotoxic Tim-3+ terminally differentiated CD8+ T cells in both tumor-draining lymph nodes (TDLNs) and the tumor microenvironment (TME), thereby enhancing the anti-tumor immune response. These findings suggest that CD69 is an attractive therapeutic target that controls the chronic anti-tumor CD8+ T cell response.
    Keywords:  CD69; chronic CD8+ T cell response; tumor‐draining lymph nodes; tumor‐specific CD8+ T cells
    DOI:  https://doi.org/10.1111/cas.70055
  3. Cell Death Discov. 2025 Mar 23. 11(1): 118
      Liver cancer is the sixth most common cancer worldwide and the third most common cause of cancer mortality. The development and progression of liver cancer and metastases is a multifaceted process involving numerous metabolic pathways. T cells have a protective role in the defense against cancer, and manipulating metabolic pathways in T cells can alter their antitumor activity. Furthermore, Liver cancer and T cell nutrition competition lead to T cell dysfunction through various molecular mechanisms. Some nanomaterials and drugs can improve T cell metabolism and promote the anti-liver cancer function of T cells. This review discusses the current literature regarding metabolic changes in liver cancer, the role of T cells in liver cancer, T cell metabolism in liver cancer, and targeted T cell metabolism therapy for liver cancer. The promise and challenges of studying target T cell metabolism for treating liver cancer are also addressed. Targeting T cell metabolism is a promising approach for treating liver cancer.
    DOI:  https://doi.org/10.1038/s41420-025-02397-w
  4. J Immunol. 2025 Mar 22. pii: vkaf009. [Epub ahead of print]
      Cytotoxic T cell (CTL) exhaustion is driven by chronic T cell receptor (TCR) stimulation, leading to a dysfunctional state of cells. Exhausted CTLs exhibit diminished effector function against chronic infections and cancers. Therefore, reducing CTL exhaustion may re-establish effective adaptive immune responses. One feature of exhausted CTLs is the sustained and stable expression of transcription factor thymocyte selection-associated high mobility group box (TOX). Downregulating TOX expression in CD8+ T cells enhances their antitumor activities and improves immune checkpoint blockade (ICB) efficiency. We generated a reporter transgenic mouse to rapidly detect the expression of TOX by measuring luciferase activity. We knocked in a reporter cassette containing NanoLuc bioluminescent luciferase (Nluc) into the Tox gene locus by CRISPR/Cas9 (Tox-NLuc mice). We further generated Tox-NLuc-OT-I mice by crossing Tox-NLuc mice with OT-I mice, which allows the induction of CTL exhaustion in vitro by repeated stimulation of CD8+ T cells with OVA (257-264) peptide. Luciferase assays showed that higher luminescent signals were detected in exhausted CTLs compared to non-exhausted CTLs, which can be visualized by bioluminescence imaging. Bioluminescence changes were confirmed by measuring TOX expression by flow cytometry. The luminescence in exhausted CTLs decreased significantly when cells treated with ibrutinib and bryostatin-1, drugs that were found to directly modulate T cell exhaustion and decrease TOX expression. In summary, we have developed a novel TOX-nanoluciferase-based reporter system that can be used to monitor TOX expression and may facilitate the screening of molecules that modulate CTL exhaustion.
    Keywords:  CD8+; CRISPR-Cas; T cells; TOX; exhaustion
    DOI:  https://doi.org/10.1093/jimmun/vkaf009
  5. Clin Immunol. 2025 Mar 20. pii: S1521-6616(25)00061-0. [Epub ahead of print]275 110486
      T cell senescence and exhaustion represent critical aspects of adaptive immune system dysfunction, with profound implications for health and the development of disease prevention and therapeutic strategies. These processes, though distinct, are interconnected at the molecular level, leading to impaired effector functions and reduced proliferative capacity of T cells. Such impairments increase susceptibility to diseases and diminish the efficacy of vaccines and treatments. Importantly, T cell senescence and exhaustion can dynamically influence each other, particularly in the context of chronic diseases. A deeper understanding of the molecular mechanisms underlying T cell senescence and exhaustion, as well as their interplay, is essential for elucidating the pathogenesis of related diseases and restoring dysfunctional immune responses. This knowledge will pave the way for the development of targeted therapeutic interventions and strategies to enhance immune competence. This review aims to summarize the characteristics, mechanisms, and disease associations of T cell senescence and exhaustion, while also delineating the distinctions and intersections between these two states to enhance our comprehension.
    Keywords:  Aging; Exhaustion; Immunosenescence; Senescence; T-lymphocytes
    DOI:  https://doi.org/10.1016/j.clim.2025.110486
  6. STAR Protoc. 2025 Mar 25. pii: S2666-1667(25)00109-1. [Epub ahead of print]6(2): 103703
      Transcription factors play a crucial role in the differentiation of tumor-specific CD8+ T cells and significantly influence their capacity to repress tumors. Here, we present a protocol for creating a transcription regulator inhibitor of DNA 3 (ID3) conditional knockout mouse in tumor-specific CD8+ T cells, induced by tamoxifen. We describe steps for examining the impact of ID3 deficiency on the differentiation of tumor-specific memory CD8+ T cells (Ttsm) and progenitors of exhausted CD8+ T cells (Tpex) in tumor-draining lymph nodes through a co-adoptive transfer assay. For complete details on the use and execution of this protocol, please refer to Ran et al.1.
    Keywords:  Cancer; Cell-based Assays; Immunology
    DOI:  https://doi.org/10.1016/j.xpro.2025.103703
  7. Cancer Res. 2025 Mar 24.
      Abnormal amino acid metabolism supports cancer cell proliferation, invasion, and immune evasion in hepatocellular carcinoma (HCC). Previous research exploring amino acid metabolism in HCC has primarily focused on how metabolic reprogramming impacts tumor cells. Here, we focused on the role of amino acid metabolism dysregulation in the crosstalk between HCC and T cells. HCC cells disrupted lysine uptake in T cells, leading to impaired T cell immunity. Lysine deprivation decreased STAT3 levels in T cells, inhibiting T cell proliferation and effector function and ultimately promoting tumor progression. Mechanistically, HCC cells outcompeted T cells for lysine by expressing high levels of the lysine transporter SLC3A2. Clinically, elevated SLC3A2 expression correlated with poor survival and was linked to dysregulated T cell functional gene signatures in HCC patients. Furthermore, the multikinase inhibitor lenvatinib induced a c-Myc-SLC3A2 regulatory axis that limited the efficacy of lenvatinib treatment. Lysine supplementation enhanced tumor sensitivity to combined treatment with lenvatinib and anti-PD-1 immunotherapy. These findings suggest that lysine supplementation is a potential therapeutic strategy for treating HCC and enhancing the sensitivity of HCC to tyrosine kinase inhibitors and immune checkpoint blockade.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-3180
  8. Cell Death Differ. 2025 Mar 26.
      SIRT7, one of the least studied members of the Sirtuins family, is an NAD+-dependent lysine deacetylase and desuccinylase. While previous studies using affinity enrichment and quantitative proteomics identified numerous lysine-deacetylated substrates of SIRT7, its lysine-desuccinylated substrates remain underexplored, limiting our understanding of its role in cellular homeostasis. Here, we demonstrated that SIRT7 is predominantly expressed in immune tissues, especially in adaptive immune cells, including T cells. Through proteomics, lysine succinylome, and acetylome analysis of spleen from wild-type (WT) and Sirt7-/- mice, we identified significant succinylation of proteins involved in the branched-chain amino acid (BCAA) catabolism pathway in Sirt7-/- mice. We further found that SIRT7 partially localizes to mitochondria, interacting with key enzymes of the BCAA catabolism pathway and promoting their desuccinylation. Sirt7 deficiency leads to enhanced BCAA catabolism, accumulation of acyl-CoA, and increased fatty acid (FA) synthesis. As T cells rely heavily on amino acid metabolism for activation, differentiation, and function, we investigated the impact of SIRT7 using a T cell-specific Sirt7 knockout mouse model (Sirt7fl/flCd4-Cre). Our results show that SIRT7 is crucial for T cell proliferation, activation, and antitumor function. Sirt7 deficiency in T cells results in the accumulation of BCAA metabolites and FAs, reduced cytotoxic cytokines secretion such as IFN-γ, and T cell exhaustion. Reducing BCAA levels with BT2, a BCKDK inhibitor, or BCAA-free treatment alleviated these effects, while FA treatment exacerbates them. Overall, our findings identify SIRT7 as a critical regulator linking BCAA and FA metabolism to T cell antitumor immunity, providing new insights into its potential as a therapeutic target.
    DOI:  https://doi.org/10.1038/s41418-025-01490-y
  9. FEBS J. 2025 Mar 25.
      The tumor microenvironment (TME) is a complex ecosystem, encompassing a variety of cellular and non-cellular elements surrounding and interacting with cancer cells, overall promoting tumor growth, immune evasion, and therapy resistance. In the context of solid tumors, factors, such as hypoxia, nutritional competition, increased stress responses, glucose demand, and PD-1 signals strongly influence metabolic alterations in the TME, highly contributing to the maintenance of a tumor-supportive and immune-suppressive milieu. Cancer cell-induced metabolic alterations partly result in an increased fatty acid (FA) metabolism within the TME, which strongly favors the recruitment of immune-suppressive M2 macrophages and myeloid-derived suppressor cells, crucial contributors to T-cell exhaustion, tumor exclusion, and decreased effector functions. The drastic pro-tumoral changes induced by the tumor metabolic rewiring result in signaling loops that support tumor progression and metastatic spreading, and negatively impact therapy efficacy. As tumor- and immune metabolism are increasingly gaining attention due to their potential therapeutic implications, we discuss the effects of altered lipid metabolism on tumor progression, immune response, and therapeutic efficacy in the context of lung cancer. In particular, we focus our analysis on the tumor-induced metabolic alterations experienced by T lymphocytes and the possible strategies to overcome immunotherapy resistance by targeting specific metabolic pathways in T cells.
    Keywords:  T‐cell function; cancer metabolism; fatty acid metabolism; lung cancer
    DOI:  https://doi.org/10.1111/febs.70081
  10. Mar Drugs. 2025 Mar 19. pii: 133. [Epub ahead of print]23(3):
      T cells play pivotal roles in inflammation's initiation and progression. Exploring natural compounds that regulate T cell function is crucial for preventing and treating inflammation. Herein, we report that Alternariol (AOH), a marine-derived secondary metabolite, exerts an anti-inflammatory activity by targeting T cell function. Using an ovalbumin (OVA)-induced OT-II CD4+ T cell activation model, we demonstrated that AOH potently suppresses T cell proliferation and cytokine secretion, mildly promotes T cell apoptosis, and spares antigen presentation processes. Mechanistically, AOH controlled early T cell activation by inhibiting the expression of activation markers (CD69, CD25, CD44) and transcription factors (T-bet, Eomes), leading to impaired Th1 cytokine production. In vivo experiments revealed that AOH attenuated OVA-induced lung injury in mice by reducing immune cell infiltration in pulmonary tissues and draining lymph nodes. Notably, AOH dramatically suppressed OVA-specific T cells migrating to the inflammatory lung while impairing T-cell-mediated other immune cell infiltration. Collectively, AOH exhibited potent anti-inflammatory effects by modulating T cell proliferation, function, and migration, offering a promising therapeutic strategy for T-cell-mediated inflammatory diseases.
    Keywords:  CD4+ T cells; alternariol; cell migration; inflammation cytokines; lung injury
    DOI:  https://doi.org/10.3390/md23030133
  11. Biology (Basel). 2025 Mar 09. pii: 279. [Epub ahead of print]14(3):
      Aging is a time-dependent process of functional decline influenced by genetic and environmental factors. Age-related mitochondrial changes remain incompletely understood. Here, we found that compared to the wild type, the mitochondria of long-lived daf-2 C. elegans maintain youthful morphology and function. Through quantitative proteomic analysis on isolated mitochondria, we identified 257 differentially expressed candidates. Analysis of these changed mitochondrial proteins reveals a significant upregulation of five key mitochondrial metabolic pathways in daf-2 mutants, including branched-chain amino acids (BCAA), reactive oxygen species (ROS), propionate, β-alanine, and fatty acids (FA), all of which are related to daf-2-mediated longevity. In addition, mitochondrial ribosome protein abundance slightly decreased in daf-2 mutants. A mild reduction in mitochondrial elongation factor G (gfm-1) by RNAi extends the lifespan of wild type while decreasing lipid metabolic process and cytoplasmic fatty acid metabolism, suggesting that proper inhibition of mitochondrial translation activity might be important for lifespan extension. Overall, our findings indicate that mitochondrial metabolic modulation contributes to the longevity of daf-2 mutants and further highlights the crucial role of mitochondria in aging.
    Keywords:  DAF-2; aging; metabolism; mitochondria; quantitative proteomics
    DOI:  https://doi.org/10.3390/biology14030279
  12. Clin Exp Med. 2025 Mar 25. 25(1): 96
      Myasthenia Gravis (MG) is a heterogeneous autoimmune disorder characterized by fluctuating muscle weakness caused by autoantibodies targeting neuromuscular junction components. While the role of CD4 + T cells in MG is well established, the contribution of CD8 + T cells remains poorly understood. In this study, we analyze CD8 + T cells in 36 MG patients and 38 age- and gender-matched controls using flow cytometry to evaluate subset distribution, granzyme expression, and cytokine production. MG patients exhibit an altered CD4 + /CD8 + T cell ratio and significant changes in CD8 + T cell subsets, including increased central memory CD8 + T cell (Tcm) proportions and decreased effector memory CD8 + T cell (Tem) proportions. Granzyme B expression in Tcm cells is significantly elevated in MG patients, whereas no significant changes are observed in other subsets or GZMK expression. Cytokine analysis reveals increased IL-21, GM-CSF, and IL-17A production by CD8 + T cells in MG patients. These phenotypic and functional alterations of CD8 + T cells persist during the acute phase of the disease, regardless of immunotherapy usage, and vary between ocular and generalized MG. Subgroup and correlation analyses further identify age-dependent and age-independent dysregulations of CD8 + T cells, indicating complex and subtype-specific roles of CD8 + T cells in the immunopathological processes underlying MG. Our findings provide novel insights into the involvement of CD8 + T cells in MG pathogenesis, laying a foundation for future research and potential therapeutic strategies targeting CD8 + T cells.
    Keywords:  CD8 + T cells; GM-CSF; Granzyme B; IL-21; Myasthenia gravis; Pathogenesis
    DOI:  https://doi.org/10.1007/s10238-025-01603-4
  13. Autoimmun Rev. 2025 Mar 23. pii: S1568-9972(25)00065-5. [Epub ahead of print]24(6): 103805
      Autoimmune diseases (AIDs) are a group of disorders in which the immune system mistakenly attacks the body's own tissues, characterized by the loss of tolerance to self-antigens and destruction of tissues. Aging is a natural process of physiological decline that also alters the immune system, a condition known as immunosenescence. During immunosenescence, the immune system undergoes various changes, including modifications and antigenicity of self-antigens, abnormalities in the quantity, phenotype, and function of lymphocytes and antibodies, as well as a narrowing of the B and T cell receptor repertoire, changes that may increase susceptibility to AIDs. Additionally, senescent immune cells and the senescence-associated secretory phenotype (SASP) contribute to target organ involvement in AIDs, exacerbating chronic inflammation and tissue damage. Mitochondrial dysfunction and metabolic imbalances in AIDs lead to the accumulation of senescent cells, which act as upstream drivers of immunosenescence. In this review, we summarize the bidirectional relationship between AIDs and immunosenescence, as well as its potential mechanisms. Therapeutic approaches targeting immunosenescence in AIDs remain at an early stage. Strategies aimed at resetting or reversing the aging immune system are expected to become a novel direction in the future.
    Keywords:  Aging; Autoimmune diseases; Autoimmunity; Immune system; Immunosenescence
    DOI:  https://doi.org/10.1016/j.autrev.2025.103805
  14. Front Pharmacol. 2025 ;16 1583986
      
    Keywords:  cancer; metabolic pathways; metabolic plasticity; metabolic reprogramming; metabolites; tumor microenvironment; tumorigenesis
    DOI:  https://doi.org/10.3389/fphar.2025.1583986
  15. Cell Rep. 2025 Mar 21. pii: S2211-1247(25)00227-X. [Epub ahead of print]44(4): 115456
      Group 3 innate lymphoid cells (ILC3s) are tissue-resident cells that sense environmental cues, control infections, and promote tissue homeostasis at mucosal surfaces. The metabolic sensor liver kinase B1 (LKB1) integrates intracellular stress, metabolism, and mitochondrial function to promote the development and effector functions of a variety of immune cells; however, the role of LKB1 in ILC3 function was unknown. Here, we show that LKB1 is crucial for adult ILC3 homeostasis, cytokine production, and mitochondrial function. ILC3-specific LKB1 deletion resulted in a reduced number of ILC3s and interleukin-22 (IL-22) production. LKB1-deficient ILC3s had decreased survival, mitochondrial dysfunction, cytoplasmic lipid accumulation, and altered bioenergetics. Using LKB1 downstream kinase modulators, we found that LKB1 regulation of ILC3 survival and IL-22 production requires signaling through microtubule affinity-regulating kinases (MARKs). Mechanistically, LKB1 deficiency resulted in increased reactive oxygen species (ROS) production and NFAT2 and PD-1 expression. Our work reveals that metabolic regulation of enteric ILC3 function by an LKB1-dependent signaling network is crucial for intestinal immunity and tissue homeostasis.
    Keywords:  CP: Immunology; CP: Metabolism; ILC3; LKB1; group 3 innate lymphoid cells; liver kinase B1; mitochondrial function
    DOI:  https://doi.org/10.1016/j.celrep.2025.115456
  16. PLoS One. 2025 ;20(3): e0320375
      Plasmodium-specific CD4+ T cells differentiate into effector and memory subsets during experimental malaria, via mechanisms that remain incompletely characterised. By mining scRNA-seq data of CD4+ T cells during Plasmodium chabaudi chabaudi AS infection in mice, we identified two genes previously uncharacterised in T helper cells, long-tailed unconventional myosin 1f (Myo1f) and proline-rich13/taxanes-resistance 1 (Prr13/Txr1), which were upregulated during effector and memory differentiation. Myo1f is reported to regulate motility and granule exocytosis in myeloid and γδ T cells. Prr13/Txr1 is reported to transcriptionally regulate sensitivity to anti-cancer drugs. To test for cell-intrinsic gene function, we generated Plasmodium-specific TCR transgenic, PbTII cells harbouring CD4-promoter driven Cre recombinase and target genes with loxP-flanked essential exons. We validated our approach for the transcription factor Maf, formally demonstrating here that cMaf is essential for T follicular helper (Tfh) cell differentiation in experimental malaria. Next, having generated conditional knockout lines for Myo1f and Prr13, we observed that deficiency in Myo1f or Prr13 had no impact on either clonal expansion, Th1/Tfh differentiation or transit to memory. Additionally, despite continued expression during re-infection, Myo1f was unnecessary for Th1 recall in vivo. Thus, while cMaf is critical for Tfh differentiation in experimental malaria, Myo1f and Prr13, although transcriptionally upregulated, are unnecessary for effector or memory CD4+ T cell responses.
    DOI:  https://doi.org/10.1371/journal.pone.0320375
  17. J Immunol. 2025 Mar 22. pii: vkaf023. [Epub ahead of print]
      Acute graft-versus-host disease (GVHD) is a donor T cell driven complication and the leading cause of non-relapse mortality in patients receiving an allogeneic hematopoietic cell transplantation (allo-HCT). Allogeneic donor T cells eradicate residual leukemia and prevent relapse via the graft-versus-leukemia (GVL) effect and are critical for responding against opportunistic infections post-transplant. Current regimens successful in preventing GVHD are broadly immunosuppressive and come at the cost of increased risk of relapse and/or infection. Therefore, there is an urgent need for new approaches that limit GVHD while retaining GVL responses. During GVHD, alloreactive T cells boost their energy production through oxidative phosphorylation (OXPHOS) and glycolysis, supporting heightened proliferation and pathogenicity against healthy host tissues. The enzyme dihydroorate dehydrogenase (DHODH), is essential for de novo pyrimidine biosynthesis and for maintaining mitochondrial membrane potential during OXPHOS. Having shown upregulation of DHODH messenger RNA and protein expression in activated human T cells, we evaluated DHODH inhibition, via a small molecule inhibitor HOSU-53, as a therapeutic approach for GVHD. Inhibiting DHODH significantly reduced oxidative metabolism in T cells both during and after activation, while selectively suppressing inflammatory cytokine production in de novo activated, but not previously activated, T cells. In a xenogeneic model, HOSU-53 treatment limited GVHD severity, decreased pathogenic Th1 and Th17 response, and preserved beneficial GVL effects. Altogether, we identify DHODH inhibition as an innovative treatment strategy in allo-HCT recipients to reduce GVHD severity and retain effective GVL response.
    Keywords:  DHODH; GVHD; metabolism
    DOI:  https://doi.org/10.1093/jimmun/vkaf023
  18. JCI Insight. 2025 Mar 25. pii: e183706. [Epub ahead of print]
      Adult stem cells decline in number and function in old age and identifying factors that can delay or revert age-associated adult stem cell dysfunction are vital for maintaining healthy lifespan. Here we show that Vitamin A, a micronutrient that is derived from diet and metabolized into retinoic acid, acts as an antioxidant and transcriptional regulator in muscle stem cells. We first show that obstruction of dietary Vitamin A in young animals drives mitochondrial and cell cycle dysfunction in muscle stem cells that mimics old age. Next, we pharmacologically targeted retinoic acid signaling in myoblasts and aged muscle stem cells ex vivo and in vivo and observed reductions in oxidative damage, enhanced mitochondrial function, and improved maintenance of quiescence through fatty acid oxidation. We next detected the receptor for vitamin A derived retinol, stimulated by retinoic acid 6 or Stra6, was diminished with muscle stem cell activation and in old age. To understand the relevance of Stra6 loss, we knocked down Stra6 and observed an accumulation of mitochondrial reactive oxygen species, as well as changes in mitochondrial morphology and respiration. These results demonstrate that Vitamin A regulates mitochondria and metabolism in muscle stem cells and highlight a unique mechanism connecting stem cell function with vitamin intake.
    Keywords:  Adult stem cells; Aging; Muscle; Muscle biology; Stem cells
    DOI:  https://doi.org/10.1172/jci.insight.183706
  19. Trends Cell Biol. 2025 Mar 26. pii: S0962-8924(25)00042-X. [Epub ahead of print]
      While mitochondrial dysfunction is one of the canonical hallmarks of aging, it remains only vaguely defined. Its core feature embraces defects in energy-producing molecular machinery, the mitochondrial respiratory complexes (MRCs). The causes and consequences of these defects hold research attention. In this review, we assess the lifecycle of respiratory complexes, from biogenesis to degradation, and look closely at the mechanisms that could underpin their dysfunction in aged cells. We discuss how these processes could be altered by aging and expand on the fate of MRCs in age-associated pathologies. Given the complexity behind MRC maintenance and functionality, several traits could contribute to the phenomenon known as age-associated mitochondrial dysfunction. New advances will help us better understand the fate of this machinery in aging and age-related diseases.
    Keywords:  OXPHOS; age-associated diseases; dysfunction; mitochondria; protein complexes, aging hallmarks
    DOI:  https://doi.org/10.1016/j.tcb.2025.02.008
  20. Emerg Microbes Infect. 2025 Dec;14(1): 2466695
      People living with HIV (PLWH) exhibit accelerated aging, characterized by systemic inflammation, termed "inflammaging." While T-cell expansion is prevalent in PLWH, its connection to inflammaging remains unclear. In this study, we analyzed the TCRβ repertoire of 257 healthy controls (HC) and 228 PLWH, revealing pronounced T cell clonal expansion in PLWH. The expansion was only partially reversed following antiretroviral therapy (ART) and closely associated with ART duration, CD4+ T and CD8+ T cell counts and the CD4/CD8 ratio. TCR-based age modeling showed a continuous accelerated trajectory of aging in PLWH, especially in younger individuals, in stark contrast to the nonlinear aging acceleration pattern seen in HC. Furthermore, using single-cell RNA combined TCR sequencing and in vitro experiments, we identified GNLY+CD8+ T cells as the primary population driving clonal expansion and maintenance in PLWH. These cells are characterized by high cytotoxicity and low exhaustion and are activated by interleukin-15 (IL-15) in vitro. Notably, GNLY+CD8+ T cells predominantly express the pro-inflammatory 15 kDa form of granulysin(GNLY). The supernatant from IL-15-stimulated CD8+ T cells induces monocytes to secrete inflammatory factors and disrupts the integrity of intestinal epithelial cells, which can be partially restored by the anti-GNLY antibodies. These findings identify GNLY+CD8+ T cells as the central drivers of persistent clonal expansion, highlighting their crucial role for mitigating inflammaging in PLWH.
    Keywords:  GNLY+CD8+ T cells; HIV; TCR repertoire; clonal expansion; inflammaging
    DOI:  https://doi.org/10.1080/22221751.2025.2466695
  21. Cancer Res. 2025 Mar 24.
      Aging is a known risk factor for melanoma, yet mechanisms underlying melanoma progression and metastasis in older populations remain largely unexplored. Aging might alter phenotypes of cells in the melanoma microenvironment, selecting for populations that support metastatic progression. Here, we demonstrated that age engenders the development of an immunosuppressive tumor microenvironment, which is linked to phenotypes associated with melanoma metastasis. Among cellular populations enriched by aging were macrophages with a tolerogenic phenotype expressing TREM2 and dysfunctional CD8+ T cells with an exhausted phenotype, while macrophages with a profibrotic phenotype expressing TREM1 were depleted. Notably, TREM1 inhibition decreased melanoma growth in young but not old mice, whereas TREM2 inhibition prevented lung metastasis in aged mice. These data identify age-related targets associated with melanoma metastasis and may guide aged-dependent immunotherapeutic strategies.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-4317