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Elimination of senescent cells with senolytic host- directed therapy reduces tuberculosis progression in mice

ABSTRACT: By eliciting lung necrosis, which enhances aerosol transmission, Mycobacterium tuberculosis (Mtb) sustains its long-term survival as a human pathogen. In studying the necrotic granuloma lesions unique tocharacteristic of Mtb-infected B6.Sst1S mice, we found that lung myeloid cells display elevated senescence markers including cell cycle arrest proteins p21 and p16, the DNA damage marker γH2A.X, senescence-associated β-Galactosidase activity, and senescence-associated secretory phenotype (SASP) proteins. These same markers were also elevated in Mtb-infected aged wild type (WT) mice but not in young WT mice. Global transcriptomics data revealed activation of pro-survival (PI3K, MAPK) and anti-apoptotic pathways in TNFα- treated and Mtb- infected B6.Sst1S BMDMs. As senescent cells have been postulated shown to be long-lived, non-dividing cells which release tissue damaging signaling molecules, we treated Mtb-infected mice with a cocktail of three senolytic drugs (dasatinib, quercetin, and fisetin) designed to kill senescent cells. Senolytic drug treatment prolonged survival and reduced Mtb lung counts in B6.Sst1S and aged WT mice to a greater degree than young WT mice and concomitantly reduced lung senescence markers. These findings indicate that (1) Mtb infection may induce lung myeloid cells to enter a senescent state and that these cells play a causal role in disease progression, and (2) Senolytics merit consideration for human clinical trials against tuberculosis (TB)Senolytics should be tested in human clinical trials against TB.

ORGANISM(S): Mus musculus

PROVIDER: GSE292458 | GEO | 2026/03/24

REPOSITORIES: GEO

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Elimination of senescent cells with senolytic host-directed therapy reduces tuberculosis progression in mice.

Project description:By eliciting lung necrosis, which enhances aerosol transmission, Mycobacterium tuberculosis (Mtb) sustains its long-term survival as a human pathogen. In studying the necrotic granuloma lesions unique tocharacteristic of Mtb-infected B6.Sst1S mice, we found that lung myeloid cells display elevated senescence markers including cell cycle arrest proteins p21 and p16, the DNA damage marker γH2A.X, senescence-associated β-Galactosidase activity, and senescence-associated secretory phenotype (SASP) proteins. These same markers were also elevated in Mtb-infected aged wild type (WT) mice but not in young WT mice. Global transcriptomics data revealed activation of pro-survival (PI3K, MAPK) and anti-apoptotic pathways in TNFα- treated and Mtb- infected B6.Sst1S BMDMs. As senescent cells have been postulated shown to be long-lived, non-dividing cells which release tissue damaging signaling molecules, we treated Mtb-infected mice with a cocktail of three senolytic drugs (dasatinib, quercetin, and fisetin) designed to kill senescent cells. Senolytic drug treatment prolonged survival and reduced Mtb lung counts in B6.Sst1S and aged WT mice to a greater degree than young WT mice and concomitantly reduced lung senescence markers. These findings indicate that (1) Mtb infection may induce lung myeloid cells to enter a senescent state and that these cells play a causal role in disease progression, and (2) Senolytics merit consideration for human clinical trials against tuberculosis (TB)Senolytics should be tested in human clinical trials against TB.

2026-03-24 | GSE301446 | GEO

Effect of small molecule inhibitors on transcriptome of B6.Sst1S bone marrow derived macrophages stimulated with TNF and infected with virulent Mycobacterium tuberculosis

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BACH1 is a central regulator of glutathione metabolism, cellular necrosis and host resistance in Mycobacterium tuberculosis infection

Project description:Background. An exacerbated oxidative stress response can regulate cellular necrosis by triggering lipid peroxidation in an iron-dependent manner and this form of necrotic death has been implicated in Mycobacterium tuberculosis (Mtb) pathogenesis. Here we examined the role of Bach1, a transcription factor that represses a major set of antioxidant genes, in regulating host resistance to Mtb. We found that BACH1 expression is associated with and predicts active pulmonary tuberculosis in humans. In response to Mtb infection in vitro and in vivo, ablation of Bach1 increased the levels of glutathione as well as enhanced the expression of Gpx4, an enzyme that regulates lipid peroxidation. Consistent with these observations, Bach1-/- macrophages exhibited increased resistance to Mtb-induced cell death and infected Bach1-deficient mice displayed a striking reduction in bacterial loads as well as pulmonary necrosis and lipid peroxidation accompanied by enhanced survival. In addition, single-cell RNAseq analysis of the lungs of Mtb-infected Bach1-/- mice revealed an enrichment of genes associated with suppression of ferroptosis. Finally, deletion of Bach1 in B6.Sst1S mice, an inbred strain that exhibits the necrotic lung pathology similar to that seen in human TB, enhanced host resistance to Mtb while significantly reducing tissue necrosis. These findings identify Bach1 and its regulation of the oxidative stress response as an important modulator of cellular and tissue necrosis as well as host resistance in Mtb infection.

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BACH1 is a central regulator of glutathione and iron metabolism, necrotic cell death and host resistance in Mycobacterium tuberculosis infection

Project description:Exacerbated oxidative stress response is known to regulate cellular necrosis by triggering lipid peroxidation in an iron-dependent manner and this form of necrotic death has been implicated in Mycobacterium tuberculosis (Mtb) infection and disease. Here we examined the role of Bach1, a transcription factor that represses a major set of antioxidant genes, in regulating host resistance to Mtb. In response to Mtb infection in vitro and in vivo, ablation of Bach1 increased the levels of glutathione as well as enhanced the expression of Gpx4, an enzyme that regulates lipid peroxidation. Consistent with these observations, Bach1-/- macrophages exhibited increased resistance to Mtb-induced necrosis and infected Bach1-deficient mice displayed a striking reduction in bacterial loads as well as pulmonary necrosis and lipid peroxidation reflected in their enhanced survival. In addition, single-cell RNAseq analysis of the lungs of Mtb-infected Bach1-/- mice revealed an enrichment of a gene signature associated with protection against ferroptotic cell death. Finally, deletion of Bach1 in B6.Sst1S mice, an inbred strain that recapitulates the necrotic lung pathology seen in human TB, enhanced host resistance to Mtb while significantly reducing tissue necrosis. These findings identify Bach1 as an important regulator of cellular and tissue necrosis in Mtb infection and as such a potential target for host-direct therapy of tuberculosis.

2023-06-30 | GSE236053 | GEO

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Project description:Cellular senescence is a stress-response program characterized by stable cell cycle arrest and a secretory program that modulates the tissue microenvironment. Physiologically, senescence serves as a potent tumor suppressive mechanism that prevents the expansion of premalignant cells and plays a beneficial role in certain wound healing responses. Pathologically, the aberrant accumulation of senescent cells in response to chronic tissue damage produces an inflammatory milieu that contributes to diseases such as liver and lung fibrosis, atherosclerosis, diabetes and osteoarthritis. Accordingly, experimental approaches to eliminate senescent cells from damaged tissues in mice can ameliorate symptoms of these pathologies and even promote longevity. Here we test the therapeutic concept that chimeric antigen receptor (CAR) T cells targeting senescent cells can serve as effective senolytics. We identify the urokinase plasminogen activator receptor (uPAR) as a cell surface protein that is broadly induced during senescence and demonstrate that uPAR-specific CAR T cells efficiently target senescent cells in vitro and in vivo. Administration of uPAR-targeting CAR T cells improves the survival of mice harboring lung adenocarcinoma cells treated with a senescence inducing drug combination, and eliminates fibrosis in mice treated with carbon tetrachloride or on a non-alcoholic steatohepatitis (NASH)-inducing diet. These results establish the potential of senolytic CAR T therapy for a range of senescence-associated diseases.

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The Effect of Senolytic (BI01) Administration on DNA Methylation Clock Age and the Methylome in Aged and Regenerated Skeletal Muscle

Project description:Background: Senescence cells emerge with aging and injury. The contribution of senescent cells to DNA methylation age (DNAmAGE) in vivo is uncertain. Furthermore, stem cell therapy can mediate “rejuvenation”, but how tissue regeneration controlled by resident stem cells affects whole tissue DNAmAGE is unclear. Methods: We assessed DNAmAGE with or without senolytics (BI01) in aged male mice (24-25 months) 35 days following muscle healing (BaCl2-induced regeneration versus non-injured). Young injured mice (5-6 months) without senolytics were comparators.Results: DNAmAGE was decelerated by up to 68% after injury in aged muscle. DNAmAGE was modestly but further significantly decelerated by injury recovery with senolytics. ~1/4 of measured CpGs were altered by injury then recovery regardless of senolytics in aged muscle. Specific methylation changes caused by senolytics included differential regulation of Col, Hdac, Hox, and Wnt genes, which likely contributed to improved regeneration. Altered extracellular matrix remodeling using histological analysis aligned to the methylomic findings with senolytics. Without senolytics, regeneration had a contrasting effect in young mice and tended not to influence or modestly accelerate DNAmAGE. Comparing young to old injury recovery without senolytics using methylome-transcriptome integration, we found a more coordinated molecular profile in young and differential regulation of genes implicated in muscle stem cell performance: Axin2, Egr1, Fzd4, Meg3, and Spry1. Conclusions: Muscle injury and senescent cells affect DNAmAGE and aging influences the transcriptomic-methylomic landscape after resident stem cell-driven tissue reformation. Our data have implications for understanding muscle plasticity with aging and developing therapies aimed at collagen remodeling and senescence.

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Senescent cell elimination modifies features of Alzheimer’s disease in 3xTg-AD mice

Project description:Cellular senescence has been associated with neurodegenerative disease and clearance of senescent cells using genetic or pharmaceutical strategies (senolytics) has demonstrated beneficial effects in mouse models investigating individual disease etiologies of Alzheimer’s disease (AD). However, it has remained unclear if senescent cell clearance in a mouse model exhibiting both plaque and tau pathologies modifies the disease state (3xTg). Here, we show that treatment with senolytics (ABT263 (navitoclax) or a combination of dasatinib and quercetin (D+Q)) or transgenic removal of p16-expressing cells (via INK-ATTAC) reduced microgliosis and ameliorated both amyloid and tau pathology in 3xTg mice. Using RNA sequencing, we found evidence that synaptic dysfunction and neuroinflammation was attenuated with senescent cell removal. Unfortunately, these beneficial effects were not seen with short-term senolytic treatment in mice with more advanced disease. Overall, our results further corroborate the beneficial effects senescent cell clearance could have on AD and highlight the importance of early intervention for treatment of this debilitating disease.

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