bims-caglex 2024-04-07 papers

bims-caglex

Biomed News

on Cellular aging and life extension

Issue of 2024‒04‒07
thirty papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño

In the land of not-unhappiness: On the state-of-the-art of targeting aging and age-related diseases by biomedical research.
Intracellular acidification and glycolysis modulate inflammatory pathway in senescent cells.
Emerging role of cellular senescence in normal lung development and perinatal lung injury.
Mapping single-cell developmental potential in health and disease with interpretable deep learning.
Protection against APOE4 -associated aging phenotypes with the longevity-promoting intervention 17α-estradiol in male mice.
scDMAE: A Generative Denoising Model Adopted Mask Strategy for scRNA-Seq Data Recovery.
Single-cell Transcriptome Analysis Identifies Senescent Osteocytes as Contributors to Bone Destruction in Breast Cancer Metastasis.
Recent Discovery and Development of Inhibitors that Target CDK9 and Their Therapeutic Indications.
Macrophage senescence in health and diseases.
SingmiR: a single-cell miRNA alignment and analysis tool.
Age-related dysregulation of the retinal transcriptome in African turquoise killifish.
Berberine inhibits NLRP3 inflammasome activation and proinflammatory macrophage M1 polarization to accelerate peripheral nerve regeneration.
Auto-sumoylation of the Ubc9 E2 SUMO-conjugating Enzyme Extends Cellular Lifespan.
Cardioprotective Response and Senescence in Aged sEH Null Female Mice Exposed to LPS.
Anti-aging effects of icariin and the underlying mechanisms: A mini-review.
Macrophage migration inhibitory factor mediates skin aging via CD74: Insights from single-cell and bulk RNA sequencing data.
Senescent-like macrophages mediate angiogenesis for endplate sclerosis via IL-10 secretion in male mice.
Inhibition of DAPK3 suppresses radiation-induced cellular senescence by activation of a PGC1α-dependent metabolism pathway in brain endothelial cells.
Neuronal CBP-1 is required for enhanced body muscle proteostasis in response to reduced translation downstream of mTOR.
Senescence-associated ß-galactosidase staining over the lifespan differs in a short- and a long-lived fish species.
Identification of genetic modifiers enhancing B7-H3-targeting CAR T cell therapy against glioblastoma through large-scale CRISPRi screening.
Methylation entropy landscape of Chinese long-lived individuals reveals lower epigenetic noise related to human healthy aging.
Understanding Age-Related Changes: Exploring the Interplay of Protein Intake, Physical Activity, and Appetite in the Ageing Population.
Cell proliferation and regeneration in the gill : By.
Harnessing Genetics to Extend Lifespan and Healthspan: Current Progress and Future Directions.
Tobacco smoke condensate-induced senescence in endothelial cells was ameliorated by colchicine treatment via suppression of NF-κB and MAPKs P38 and ERK pathways activation.
Pancreatic cancer: new approaches to drug therapy.
[Is Biological Aging a Treatable Disease? A Consideration Based on Proposed Mechanisms of Aging].
ECM and epithelial stem cells: the scaffold of destiny.
Adeno-associated virus as a delivery vector for gene therapy of human diseases.

Mech Ageing Dev. 2024 Mar 30. pii: S0047-6374(24)00029-0. [Epub ahead of print]219 111929

In the land of not-unhappiness: On the state-of-the-art of targeting aging and age-related diseases by biomedical research.

Eirini Klinaki, Mikolaj Ogrodnik.

  The concept of the Land of Not-Unhappiness refers to the potential achievement of eliminating the pathologies of the aging process. To inform of how close we are to settling in the land, we summarize and review the achievements of research on anti-aging interventions over the last hundred years with a specific focus on strategies that slow down metabolism, compensate for aging-related losses, and target a broad range of age-related diseases. We critically evaluate the existing interventions labeled as "anti-aging," such as calorie restriction, exercise, stem cell administration, and senolytics, to provide a down-to-earth evaluation of their current applicability in counteracting aging. Throughout the text, we have maintained a light tone to make it accessible to non-experts in biogerontology, and provide a broad overview for those considering conducting studies, research, or seeking to understand the scientific basis of anti-aging medicine.

Keywords:  Age-related diseases; Aging; Anti-aging interventions; Biogerontology; Healthspan; Senescence

DOI:  https://doi.org/10.1016/j.mad.2024.111929
J Biochem. 2024 Apr 02. pii: mvae032. [Epub ahead of print]

Intracellular acidification and glycolysis modulate inflammatory pathway in senescent cells.

Satoshi Kawakami, Yoshikazu Johmura, Makoto Nakanishi.

  Senescent cells accumulate in various organs with aging, and its accumulation induces chronic inflammation and age-related physiological dysfunctions. Several remodeling of intracellular environments has been identified in senescent cells, including enlargement of cell / nuclear size and intracellular acidification. Although these alterations of intracellular environments were reported to be involved in unique characteristics of senescent cells, the contribution of intracellular acidification to senescence-associated cellular phenotypes is poorly understood. Here, we identified that upregulation of TXNIP and its paralog ARRDC4 as a hallmark of intracellular acidification in addition to KGA-type GLS1. These genes were also upregulated in response to senescence-associated intracellular acidification. Neutralization of the intracellular acidic environment ameliorated not only senescence-related upregulation of TXNIP, ARRDC4, and KGA, but also inflammation-related genes, possibly through suppression of PDK-dependent anaerobic glycolysis. Furthermore, we found that expression of the intracellular acidification-induced genes, TXNIP and ARRDC4, correlated with inflammatory gene expression in heterogeneous senescent cell population in vitro and even in vivo, implying that the contribution of intracellular pH to senescence-associated cellular features, such as SASP.

Keywords:  SASP; glycolysis; intracellular acidification; senescence

DOI:  https://doi.org/10.1093/jb/mvae032
Chin Med J Pulm Crit Care Med. 2024 Mar;2(1): 10-16

Emerging role of cellular senescence in normal lung development and perinatal lung injury.

Phyllis A Dennery, Hongwei Yao.

  Cellular senescence is a status of irreversible growth arrest, which can be triggered by the p53/p21cip1 and p16INK4/Rb pathways via intrinsic and external factors. Senescent cells are typically enlarged and flattened, and characterized by numerous molecular features. The latter consists of increased surfaceome, increased residual lysosomal activity at pH 6.0 (manifested by increased activity of senescence-associated beta-galactosidase [SA-β-gal]), senescence-associated mitochondrial dysfunction, cytoplasmic chromatin fragment, nuclear lamin b1 exclusion, telomere-associated foci, and the senescence-associated secretory phenotype. These features vary depending on the stressor leading to senescence and the type of senescence. Cellular senescence plays pivotal roles in organismal aging and in the pathogenesis of aging-related diseases. Interestingly, senescence can also both promote and inhibit wound healing processes. We recently report that senescence as a programmed process contributes to normal lung development. Lung senescence is also observed in Down Syndrome, as well as in premature infants with bronchopulmonary dysplasia and in a hyperoxia-induced rodent model of this disease. Furthermore, this senescence results in neonatal lung injury. In this review, we briefly discuss the molecular features of senescence. We then focus on the emerging role of senescence in normal lung development and in the pathogenesis of bronchopulmonary dysplasia as well as putative signaling pathways driving senescence. Finally, we discuss potential therapeutic approaches targeting senescent cells to prevent perinatal lung diseases.

Keywords:  Bronchopulmonary dysplasia; Down syndrome; Normal lung development; Senescence; Senolytics

DOI:  https://doi.org/10.1016/j.pccm.2024.01.001
bioRxiv. 2024 Mar 21. pii: 2024.03.19.585637. [Epub ahead of print]

Mapping single-cell developmental potential in health and disease with interpretable deep learning.

Minji Kang, Jose Juan Almagro Armenteros, Gunsagar S Gulati, Rachel Gleyzer, Susanna Avagyan, Erin L Brown, Wubing Zhang, Abul Usmani, Noah Earland, Zhenqin Wu, James Zou, Ryan C Fields, David Y Chen, Aadel A Chaudhuri, Aaron M Newman.

Single-cell RNA sequencing (scRNA-seq) has transformed our understanding of cell fate in developmental systems. However, identifying the molecular hallmarks of potency - the capacity of a cell to differentiate into other cell types - has remained challenging. Here, we introduce CytoTRACE 2, an interpretable deep learning framework for characterizing potency and differentiation states on an absolute scale from scRNA-seq data. Across 31 human and mouse scRNA-seq datasets encompassing 28 tissue types, CytoTRACE 2 outperformed existing methods for recovering experimentally determined potency levels and differentiation states covering the entire range of cellular ontogeny. Moreover, it reconstructed the temporal hierarchy of mouse embryogenesis across 62 timepoints; identified pan-tissue expression programs that discriminate major potency levels; and facilitated discovery of cellular phenotypes in cancer linked to survival and immunotherapy resistance. Our results illuminate a fundamental feature of cell biology and provide a broadly applicable platform for delineating single-cell differentiation landscapes in health and disease.

DOI: https://doi.org/10.1101/2024.03.19.585637
bioRxiv. 2024 Mar 14. pii: 2024.03.12.584678. [Epub ahead of print]

Protection against APOE4 -associated aging phenotypes with the longevity-promoting intervention 17α-estradiol in male mice.

Cassandra J McGill, Amy Christensen, Wenjie Qian, Max A Thorwald, Jose Godoy Lugo, Sara Namvari, Olivia S White, Caleb E Finch, Bérénice A Benayoun, Christian J Pike.

The apolipoprotein ε4 allele ( APOE4 ) is associated with decreased longevity, increased vulnerability to age-related declines, and disorders across multiple systems. Interventions that promote healthspan and lifespan represent a promising strategy to attenuate the development of APOE4 -associated aging phenotypes. Here we studied the ability of the longevity-promoting intervention 17α-estradiol (17αE2) to protect against age-related impairments in APOE4 versus the predominant APOE3 genotype using early middle-aged mice with knock-in of human APOE alleles. Beginning at age 10 months, male APOE3 or APOE4 mice were treated for 20 weeks with 17αE2 or vehicle then compared for indices of aging phenotypes body-wide. Across peripheral and neural measures, APOE4 was associated with poorer outcomes. Notably, 17αE2 treatment improved outcomes in a genotype-dependent manner favoring APOE4 mice. These data demonstrate a positive APOE4 bias in 17αE2-mediated healthspan actions, suggesting that longevity-promoting interventions may be useful in mitigating deleterious age-related risks associated with APOE4 genotype.

DOI: https://doi.org/10.1101/2024.03.12.584678
IEEE J Biomed Health Inform. 2024 Apr 03. PP

scDMAE: A Generative Denoising Model Adopted Mask Strategy for scRNA-Seq Data Recovery.

Wei Liu, Youze Pan, Zhijie Teng, Junlin Xu.

The advent of single-cell RNA sequencing (scRNA-seq) technology has revolutionized gene expression studies at the single-cell level. However, the presence of technical noise and data sparsity in scRNA-seq often undermines the accuracy of subsequent analyses. Existing methods for denoising and imputing scRNA-seq data often rely on stringent assumptions about data distribution, limiting the effectiveness of data recovery. In this study, we propose the scDMAE model for denoising and recovery of scRNA-seq data. First, the model fuses gene expression features and topological features to discern the primary expression patterns of genes in cells. Then, an autoencoder with a masking strategy is used to model dropout events and separate potential noise in the data. Finally, the model incorporates the original raw data to recover the true biological expression value. By conducting experiments on various types of scRNA-Seq datasets, scDMAE demonstrates superior performance compared to other comparative methods based on six distinct evaluation metrics in downstream analysis. The scDMAE method can accurately cluster similar cell populations, identify differential genes and infer cell trajectories.

DOI: https://doi.org/10.1109/JBHI.2024.3383921
Res Sq. 2024 Mar 14. pii: rs.3.rs-4047486. [Epub ahead of print]

Single-cell Transcriptome Analysis Identifies Senescent Osteocytes as Contributors to Bone Destruction in Breast Cancer Metastasis.

Jesus Delgado-Calle, Manish Adhikari, Japneet Kaur, Hayley Sabol, Aric Anloague, Sharmin Khan, Noriyoshi Kurihara, Marta Diaz-delCastillo, Christina Andreasen, C Lowry Barnes, Jeffrey Stambough, Michela Palmieri, Olivia Reyes-Castro, Elena Ambrogini, Maria Almeida, Charles O'Brien, Intawat Nookaew.

Breast cancer bone metastases increase fracture risk and are a major cause of morbidity and mortality among women. Upon colonization by tumor cells, the bone microenvironment undergoes profound reprogramming to support cancer progression that disrupts the balance between osteoclasts and osteoblasts, leading to bone lesions. Whether such reprogramming affects matrix-embedded osteocytes remains poorly understood. Here, we demonstrate that osteocytes in breast cancer bone metastasis develop premature senescence and a distinctive senescence-associated secretory phenotype (SASP) that favors bone destruction. Single-cell RNA sequencing identified osteocytes from mice with breast cancer bone metastasis enriched in senescence and SASP markers and pro-osteoclastogenic genes. Using multiplex in situ hybridization and AI-assisted analysis, we detected osteocytes with senescence-associated distension of satellites, telomere dysfunction, and p16 Ink4a expression in mice and patients with breast cancer bone metastasis. In vitro and ex vivo organ cultures showed that breast cancer cells promote osteocyte senescence and enhance their osteoclastogenic potential. Clearance of senescent cells with senolytics suppressed bone resorption and preserved bone mass in mice with breast cancer bone metastasis. These results demonstrate that osteocytes undergo pathological reprogramming by breast cancer cells and identify osteocyte senescence as an initiating event triggering bone destruction in breast cancer metastases.

DOI: https://doi.org/10.21203/rs.3.rs-4047486/v1
J Med Chem. 2024 Apr 02.

Recent Discovery and Development of Inhibitors that Target CDK9 and Their Therapeutic Indications.

Yuming Zhang, Lianhai Shan, Wentao Tang, Yating Ge, ChengXian Li, Jifa Zhang.

CDK9 is a cyclin-dependent kinase that plays pivotal roles in multiple cellular functions including gene transcription, cell cycle regulation, DNA damage repair, and cellular differentiation. Targeting CDK9 is considered an attractive strategy for antitumor therapy, especially for leukemia and lymphoma. Several potent small molecule inhibitors, exemplified by TG02 (4), have progressed to clinical trials. However, many of them face challenges such as low clinical efficacy and multiple adverse reactions and may necessitate the exploration of novel strategies to lead to success in the clinic. In this perspective, we present a comprehensive overview of the structural characteristics, biological functions, and preclinical status of CDK9 inhibitors. Our focus extends to various types of inhibitors, including pan-inhibitors, selective inhibitors, dual-target inhibitors, degraders, PPI inhibitors, and natural products. The discussion encompasses chemical structures, structure-activity relationships (SARs), biological activities, selectivity, and therapeutic potential, providing detailed insight into the diverse landscape of CDK9 inhibitors.

DOI: https://doi.org/10.1021/acs.jmedchem.4c00312
Acta Pharm Sin B. 2024 Apr;14(4): 1508-1524

Macrophage senescence in health and diseases.

Longling Wang, Wenxiang Hong, Hong Zhu, Qiaojun He, Bo Yang, Jiajia Wang, Qinjie Weng.

  Macrophage senescence, manifested by the special form of durable cell cycle arrest and chronic low-grade inflammation like senescence-associated secretory phenotype, has long been considered harmful. Persistent senescence of macrophages may lead to maladaptation, immune dysfunction, and finally the development of age-related diseases, infections, autoimmune diseases, and malignancies. However, it is a ubiquitous, multi-factorial, and dynamic complex phenomenon that also plays roles in remodeled processes, including wound repair and embryogenesis. In this review, we summarize some general molecular changes and several specific biomarkers during macrophage senescence, which may bring new sight to recognize senescent macrophages in different conditions. Also, we take an in-depth look at the functional changes in senescent macrophages, including metabolism, autophagy, polarization, phagocytosis, antigen presentation, and infiltration or recruitment. Furthermore, some degenerations and diseases associated with senescent macrophages as well as the mechanisms or relevant genetic regulations of senescent macrophages are integrated, not only emphasizing the possibility of regulating macrophage senescence to benefit age-associated diseases but also has an implication on the finding of potential targets or drugs clinically.

Keywords:  Age-associated diseases; Aging tissues; Drug treatment; Functional alterations; Genetic regulation; Macrophages; Molecular changes; Senescence

DOI:  https://doi.org/10.1016/j.apsb.2024.01.008
Nucleic Acids Res. 2024 Apr 04. pii: gkae225. [Epub ahead of print]

SingmiR: a single-cell miRNA alignment and analysis tool.

Annika Engel, Shusruto Rishik, Pascal Hirsch, Verena Keller, Tobias Fehlmann, Fabian Kern, Andreas Keller.

Single-cell RNA sequencing (RNA-seq) has revolutionized our understanding of cell biology, developmental and pathophysiological molecular processes, paving the way toward novel diagnostic and therapeutic approaches. However, most of the gene regulatory processes on the single-cell level are still unknown, including post-transcriptional control conferred by microRNAs (miRNAs). Like the established single-cell gene expression analysis, advanced computational expertise is required to comprehensively process newly emerging single-cell miRNA-seq datasets. A web server providing a workflow tailored for single-cell miRNA-seq data with a self-explanatory interface is currently not available. Here, we present SingmiR, enabling the rapid (pre-)processing and quantification of human miRNAs from noncoding single-cell samples. It performs read trimming for different library preparation protocols, generates automated quality control reports and provides feature-normalized count files. Numerous standard and advanced analyses such as dimension reduction, clustered feature heatmaps, sample correlation heatmaps and differential expression statistics are implemented. We aim to speed up the prototyping pipeline for biologists developing single-cell miRNA-seq protocols on small to medium-sized datasets. SingmiR is freely available to all users without the need for a login at https://www.ccb.uni-saarland.de/singmir.

DOI: https://doi.org/10.1093/nar/gkae225
bioRxiv. 2024 Mar 11. pii: 2024.02.21.581372. [Epub ahead of print]

Age-related dysregulation of the retinal transcriptome in African turquoise killifish.

Steven Bergmans, Nicole C L Noel, Luca Masin, Ellen G Harding, Aleksandra M Krzywańska, Julie D De Schutter, Rajagopal Ayana, Chi-Kuo Hu, Lut Arckens, Philip A Ruzycki, Ryan B MacDonald, Brian S Clark, Lieve Moons.

  Age-related vision loss caused by retinal neurodegenerative pathologies is becoming more prevalent in our ageing society. To understand the physiological and molecular impact of ageing on retinal homeostasis, we used the short-lived African turquoise killifish, a model known to naturally develop central nervous system (CNS) ageing hallmarks and vision loss. Bulk and single-cell RNA-sequencing (scRNA-seq) of three age groups (6-, 12-, and 18-week-old) identified transcriptional ageing fingerprints in the killifish retina, unveiling pathways also identified in the aged brain, including oxidative stress, gliosis, and inflammageing. These findings were comparable to observations in ageing mouse retina. Additionally, transcriptional changes in genes related to retinal diseases, such as glaucoma and age-related macular degeneration, were observed. The cellular heterogeneity in the killifish retina was characterised, confirming the presence of all typical vertebrate retinal cell types. Data integration from age-matched samples between the bulk and scRNA-seq experiments revealed a loss of cellular specificity in gene expression upon ageing, suggesting potential disruption in transcriptional homeostasis. Differential expression analysis within the identified cell types highlighted the role of glial/immune cells as important stress regulators during ageing. Our work emphasises the value of the fast-ageing killifish in elucidating molecular signatures in age-associated retinal disease and vision decline. This study contributes to the understanding of how age-related changes in molecular pathways may impact CNS health, providing insights that may inform future therapeutic strategies for age-related pathologies.

Keywords:  Ageing; Gliosis; Inflammageing; Neurodegeneration; Nothobranchius furzeri; Oxidative stress; Retina; Transcriptomics

DOI:  https://doi.org/10.1101/2024.02.21.581372
Neurotherapeutics. 2024 Apr 02. pii: S1878-7479(24)00033-3. [Epub ahead of print] e00347

Berberine inhibits NLRP3 inflammasome activation and proinflammatory macrophage M1 polarization to accelerate peripheral nerve regeneration.

Jun Sun, Qiuhua Zeng, Zhimin Wu, Lixin Huang, Tao Sun, Cong Ling, Baoyu Zhang, Chuan Chen, Hui Wang.

  Berberine (BBR) has demonstrated potent anti-inflammatory effects by modulating macrophage polarization. Nevertheless, the precise mechanisms through which berberine regulates post-injury inflammation within the peripheral nerve system remain elusive. This study seeks to elucidate the role of BBR and its underlying mechanisms in inflammation following peripheral nerve injury (PNI). Adult male C57BL/6J mice subjected to PNI were administered daily doses of berberine (0, 60, 120, 180, 240 mg/kg) via gavage from day 1 through day 28. Evaluation of the sciatic function index (SFI) and paw withdrawal threshold revealed that BBR dose-dependently enhanced both motor and sensory functions. Immunofluorescent staining for anti-myelin basic protein (anti-MBP) and anti-neurofilament-200 (anti-NF-200), along with histological staining comprising hematoxylin-eosin (HE), luxol fast blue (LFB), and Masson staining, demonstrated that BBR dose-dependently promoted structural regeneration. Molecular analyses including qRT-PCR, Western blotting, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence confirmed that inactivation of the NLRP3 inflammasome by MCC950 shifted macrophages from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, while also impeding macrophage infiltration. Furthermore, BBR significantly downregulated the expression of the NLRP3 inflammasome and its associated molecules in macrophages, thereby mitigating NLRP3 inflammasome activation-induced macrophage M1 polarization and inflammation. In summary, BBR's neuroprotective effects were concomitant with the suppression of inflammation after PNI, achieved through the inhibition of NLRP3 inflammasome activation-induced macrophage M1 polarization.

Keywords:  Berberine; Inflammation; Macrophage polarization; NLRP3 inflammasome; Peripheral nerve injury

DOI:  https://doi.org/10.1016/j.neurot.2024.e00347
Res Sq. 2024 Mar 21. pii: rs.3.rs-4016606. [Epub ahead of print]

Auto-sumoylation of the Ubc9 E2 SUMO-conjugating Enzyme Extends Cellular Lifespan.

Hong-Yeoul Ryu, Dong-Won Jeong, Seung Yeon Kim, Seok-Won Jeoung, Dejian Zhao, James Knight, TuKiet Lam, Jong Hwa Jin, Hyun-Shik Lee, Mark Hochstrasser.

Calorie restriction (CR) provides anti-aging benefits through diverse processes, such as reduced metabolism and growth and increased mitochondrial activity. Although controversy still exists regarding CR-mediated lifespan effects, many researchers are seeking interventions that mimic the effects of CR. Yeast has proven to be a useful model system for aging studies, including CR effects. We report here that yeast adapted through in vitro evolution to the severe cellular stress caused by loss of the Ulp2 SUMO-specific protease exhibit both enhanced growth rates and replicative lifespan, and they have altered gene expression profiles similar to those observed in CR. Notably, in certain evolved ulp2Δ lines, a dramatic increase in the auto-sumoylation of Ubc9 E2 SUMO-conjugating enzyme results in altered regulation of multiple targets involved in energy metabolism and translation at both transcriptional and post-translational levels. This increase is essential for the survival of aged cells and CR-mediated lifespan extension. Thus, we suggest that high Ubc9 auto-sumoylation exerts potent anti-aging effects by promoting efficient energy metabolism-driven improvements in cell replication abilities. This potential could be therapeutically explored for the development of novel CR-mimetic strategies.

DOI: https://doi.org/10.21203/rs.3.rs-4016606/v1
Am J Physiol Heart Circ Physiol. 2024 Apr 05.

Cardioprotective Response and Senescence in Aged sEH Null Female Mice Exposed to LPS.

Ala Yousef, Deanna K Sosnowski, Liye Fang, Renald James Legaspi, Jacob Korodimas, Andy Lee, Katharine E Magor, John M Seubert.

  Deterioration of physiological systems, like the cardiovascular system, occurs progressively with age impacting an individual's health and increasing susceptibility to injury and disease. Cellular senescence has an underlying role in age-related alterations and can be triggered by natural aging or prematurely by stressors such as the bacterial toxin, lipopolysaccharide (LPS). The metabolism of polyunsaturated fatty acids (PUFAs) by CYP450 enzymes produces numerous bioactive lipid mediators that can be further metabolized by soluble epoxide hydrolase (sEH) into diol metabolites, often with reduced biological effects. In our study, we observed age-related cardiac differences in female mice, where young mice demonstrated resistance to LPS injury, and genetic deletion or pharmacological inhibition of sEH using trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (tAUCB) attenuated LPS-induced cardiac dysfunction in aged female mice. Bulk RNA-sequencing analyses revealed transcriptomics differences in aged female hearts. Confirmatory analysis demonstrated changes to inflammatory and senescence genes markers such as Il-6, Mcp1, Il-1β, Nlrp3, p21, p16, SA-β-gal, and Gdf15 were attenuated in the hearts of aged female mice where sEH was deleted or inhibited. Collectively, these findings highlight the role of sEH in modulating the aging process of the heart, whereby targeting sEH is cardioprotective.

Keywords:  Aging; Female; Heart; Senescence; Soluble Epoxide Hydrolase

DOI:  https://doi.org/10.1152/ajpheart.00706.2023
Aging Med (Milton). 2024 Feb;7(1): 90-95

Anti-aging effects of icariin and the underlying mechanisms: A mini-review.

Ying Li, Zhi-Feng Wei, Long Su.

  Aging is an extremely intricate and progressive phenomenon that is implicated in many physiological and pathological conditions. Icariin (ICA) is the main active ingredient of Epimedium and has exhibited multiple bioactivities, such as anti-tumor, neuroprotective, antioxidant, anti-inflammatory, and anti-aging properties. ICA could extend healthspan in both invertebrate and vertebrate models. In this review, the roles of ICA in protection from declined reproductive function, neurodegeneration, osteoporosis, aging intestinal microecology, and senescence of cardiovascular system will be summarized. Furthermore, the underlying mechanisms of ICA-mediated anti-aging effects will be introduced. Finally, we will discuss some key aspects that constrain the usage of ICA in clinical practice and the corresponding strategies to solve these issues.

Keywords:  aging; anti‐aging effects; icariin; mechanisms; senescence

DOI:  https://doi.org/10.1002/agm2.12284
Clin Immunol. 2024 Mar 31. pii: S1521-6616(24)00090-1. [Epub ahead of print] 110199

Macrophage migration inhibitory factor mediates skin aging via CD74: Insights from single-cell and bulk RNA sequencing data.

Songjiang Wu, Yujie Ouyang, Yibo Hu, Ling Jiang, Chuhan Fu, Li Lei, Yushan Zhang, Haoran Guo, Jinhua Huang, Jing Chen, Qinghai Zeng.

  Cell-cell communication is crucial for regulating signaling and cellular function. However, the precise cellular and molecular changes remain poorly understood in skin aging. Based on single-cell and bulk RNA data, we explored to assess the role of cell-cell ligand-receptor interaction in skin aging. We found that the macrophage migration inhibitory factor (MIF)/CD74 was significantly upregulated and frequent interactions were observed on fibroblasts in aged skin. Enrichment analysis and in vitro experiment revealed a close association of the activation of the MIF/CD74 with inflammatory pathways and immune response. Mechanistically, MIF/CD74 could significantly inhibit PPARγ protein, which thus significantly increased the degree of senescence of fibroblasts, and significantly up-regulated the expression of senescence-associated secretory phenotype (SASP) factors and FOS gene. Therefore, our study revealed that MIF/CD74 inhibits the activation of the PPAR signaling pathway, subsequently inducing the production of SASP factors and the upregulation of FOS expression, which accelerated fibroblast senescence.

Keywords:  CD74; Fibroblast; MIF; Peroxisome proliferation activator receptor γ; Skin aging

DOI:  https://doi.org/10.1016/j.clim.2024.110199
Nat Commun. 2024 Apr 05. 15(1): 2939

Senescent-like macrophages mediate angiogenesis for endplate sclerosis via IL-10 secretion in male mice.

Yonggang Fan, Weixin Zhang, Xiusheng Huang, Mingzhe Fan, Chenhao Shi, Lantian Zhao, Guofu Pi, Huafeng Zhang, Shuangfei Ni.

Endplate sclerosis is a notable aspect of spine degeneration or aging, but the mechanisms remain unclear. Here, we report that senescent macrophages accumulate in the sclerotic endplates of lumbar spine instability (LSI) or aging male mouse model. Specifically, knockout of cdkn2a (p16) in macrophages abrogates LSI or aging-induced angiogenesis and sclerosis in the endplates. Furthermore, both in vivo and in vitro studies indicate that IL-10 is the primary elevated cytokine of senescence-related secretory phenotype (SASP). Mechanistically, IL-10 increases pSTAT3 in endothelial cells, leading to pSTAT3 directly binding to the promoters of Vegfa, Mmp2, and Pdgfb to encourage their production, resulting in angiogenesis. This study provides information on understanding the link between immune senescence and endplate sclerosis, which might be useful for therapeutic approaches.

DOI: https://doi.org/10.1038/s41467-024-47317-1
J Gerontol A Biol Sci Med Sci. 2024 Apr 02. pii: glae088. [Epub ahead of print]

Inhibition of DAPK3 suppresses radiation-induced cellular senescence by activation of a PGC1α-dependent metabolism pathway in brain endothelial cells.

Ji-Eun Park, Jeong Woo Park, Myong-Kyu Sim, So Ra Kim, Kwang Seok Kim.

  In the brain, environmental changes, such as neuroinflammation, can induce senescence, characterized by the decreased proliferation of neurons and dendrites and synaptic and vascular damage, resulting in cognitive decline. Senescence promotes neuroinflammatory disorders by senescence-associated secretory phenotypes and ROS. In human brain microvascular endothelial cells (HBMVECs), we demonstrate that chronological aging and irradiation increase death-associated protein kinase 3 (DAPK3) expression. To confirm the role of DAPK3 in HBMVEC senescence, we disrupted DAPK3 activity using small interfering RNA (siRNA) or a dominant-negative mutant (DAPK3-P216S), which reduced cellular senescence phenotypes, as assessed by changes in tube formation, senescence-associated beta-galactosidase activity, and cell proliferation. In endothelial cells, DAPK3 promotes cellular senescence by regulating the phosphorylation and inactivation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) via the protein kinase B pathway, resulting in the decreased expression of mitochondrial metabolism-associated genes, such as ATP5G1, BDNF, and COX5A. Our studies show that DAPK3 is involved in cellular senescence and PGC1α regulation, suggesting that DAPK3 regulation may be important for treating aging-related brain diseases or the response to radiation therapy.

Keywords:  DAPK3; brain aging; cellular senescence; endothelial cell; metabolic decline

DOI:  https://doi.org/10.1093/gerona/glae088
bioRxiv. 2024 Mar 17. pii: 2024.03.15.585263. [Epub ahead of print]

Neuronal CBP-1 is required for enhanced body muscle proteostasis in response to reduced translation downstream of mTOR.

Santina Snow, Dilawar Mir, Zhengxin Ma, Jordan Horrocks, Matthew Cox, Marissa Ruzga, Hussein Sayed, Aric N Rogers.

Background: The ability to maintain muscle function decreases with age and loss of proteostatic function. Diet, drugs, and genetic interventions that restrict nutrients or nutrient signaling help preserve long-term muscle function and slow age-related decline. Previously, it was shown that attenuating protein synthesis downstream of the mechanistic target of rapamycin (mTOR) gradually increases expression of heat shock response (HSR) genes in a manner that correlates with increased resilience to protein unfolding stress. Here, we investigate the role of specific tissues in mediating the cytoprotective effects of low translation.Methods: This study uses genetic tools (transgenic C. elegans , RNA interference and gene expression analysis) as well as physiological assays (survival and paralysis assays) in order to better understand how specific tissues contribute to adaptive changes involving cellular cross-talk that enhance proteostasis under low translation conditions.
Results: We use the C. elegans system to show that lowering translation in neurons or the germline increases heat shock gene expression and survival under conditions of heat stress. In addition, we find that low translation in these tissues protects motility in a body muscle-specific model of proteotoxicity that results in paralysis. Low translation in neurons or germline also results in increased expression of certain muscle regulatory and structural genes, reversing reduced expression normally observed with aging in C. elegans . Enhanced resilience to protein unfolding stress requires neuronal expression of cbp-1 .
Conclusion: Low translation in either neurons or the germline orchestrate protective adaptation in other tissues, including body muscle.

DOI: https://doi.org/10.1101/2024.03.15.585263
Eur J Histochem. 2024 Feb 29. 68(1):

Senescence-associated ß-galactosidase staining over the lifespan differs in a short- and a long-lived fish species.

Simon Schöfer, Sylvia Laffer, Stefanie Kirchberger, Michael Kothmayer, Renate Löhnert, Elmar E Ebner, Klara Weipoltshammer, Martin Distel, Oliver Pusch, Christian Schöfer.

During the aging process, cells can enter cellular senescence, a state in which cells leave the cell cycle but remain viable. This mechanism is thought to protect tissues from propagation of damaged cells and the number of senescent cells has been shown to increase with age. The speed of aging determines the lifespan of a species and it varies significantly in different species. To assess the progress of cellular senescence during lifetime, we performed a comparative longitudinal study using histochemical detection of the senescence-associated beta-galactosidase as senescence marker to map the staining patterns in organs of the long-lived zebrafish and the short-lived turquoise killifish using light- and electron microscopy. We compared age stages corresponding to human stages of newborn, childhood, adolescence, adult and old age. We found tissue-specific but conserved signal patterns with respect to organ distribution. However, we found dramatic differences in the onset of tissue staining. The stained zebrafish organs show little to no signal at newborn age followed by a gradual increase in signal intensity, whereas the organs of the short-lived killifish show an early onset of staining already at newborn stage, which remains conspicuous at all age stages. The most prominent signal was found in liver, intestine, kidney and heart, with the latter showing the most prominent interspecies divergence in onset of staining and in staining intensity. In addition, we found staining predominantly in epithelial cells, some of which are post-mitotic, such as the intestinal epithelial lining. We hypothesize that the association of the strong and early-onset signal pattern in the short-lived killifish is consistent with a protective mechanism in a fast growing species. Furthermore, we believe that staining in post-mitotic cells may play a role in maintaining tissue integrity, suggesting different roles for cellular senescence during life.

DOI: https://doi.org/10.4081/ejh.2024.3977
J Exp Clin Cancer Res. 2024 Apr 01. 43(1): 95

Identification of genetic modifiers enhancing B7-H3-targeting CAR T cell therapy against glioblastoma through large-scale CRISPRi screening.

Xing Li, Shiyu Sun, Wansong Zhang, Ziwei Liang, Yitong Fang, Tianhu Sun, Yong Wan, Xingcong Ma, Shuqun Zhang, Yang Xu, Ruilin Tian.

  BACKGROUND: Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a poor prognosis. Current treatment options are limited and often ineffective. CAR T cell therapy has shown success in treating hematologic malignancies, and there is growing interest in its potential application in solid tumors, including GBM. However, current CAR T therapy lacks clinical efficacy against GBM due to tumor-related resistance mechanisms and CAR T cell deficiencies. Therefore, there is a need to improve CAR T cell therapy efficacy in GBM.METHODS: We conducted large-scale CRISPR interference (CRISPRi) screens in GBM cell line U87 MG cells co-cultured with B7-H3 targeting CAR T cells to identify genetic modifiers that can enhance CAR T cell-mediated tumor killing. Flow cytometry-based tumor killing assay and CAR T cell activation assay were performed to validate screening hits. Bioinformatic analyses on bulk and single-cell RNA sequencing data and the TCGA database were employed to elucidate the mechanism underlying enhanced CAR T efficacy upon knocking down the selected screening hits in U87 MG cells.
RESULTS: We established B7-H3 as a targetable antigen for CAR T therapy in GBM. Through large-scale CRISPRi screening, we discovered genetic modifiers in GBM cells, including ARPC4, PI4KA, ATP6V1A, UBA1, and NDUFV1, that regulated the efficacy of CAR T cell-mediated tumor killing. Furthermore, we discovered that TNFSF15 was upregulated in both ARPC4 and NDUFV1 knockdown GBM cells and revealed an immunostimulatory role of TNFSF15 in modulating tumor-CAR T interaction to enhance CAR T cell efficacy.
CONCLUSIONS: Our study highlights the power of CRISPR-based genetic screening in investigating tumor-CAR T interaction and identifies potential druggable targets in tumor cells that confer resistance to CAR T cell killing. Furthermore, we devised targeted strategies that synergize with CAR T therapy against GBM. These findings shed light on the development of novel combinatorial strategies for effective immunotherapy of GBM and other solid tumors.

Keywords:  B7-H3; CAR T cell; CRISPR screening; Glioblastoma multiforme; TNFSF15

DOI:  https://doi.org/10.1186/s13046-024-03027-6
Aging Cell. 2024 Apr 02. e14163

Methylation entropy landscape of Chinese long-lived individuals reveals lower epigenetic noise related to human healthy aging.

Hao-Tian Wang, Fu-Hui Xiao, Zong-Liang Gao, Li-Yun Guo, Li-Qin Yang, Gong-Hua Li, Qing-Peng Kong.

  The transition from ordered to noisy is a significant epigenetic signature of aging and age-related disease. As a paradigm of healthy human aging and longevity, long-lived individuals (LLI, >90 years old) may possess characteristic strategies in coping with the disordered epigenetic regulation. In this study, we constructed high-resolution blood epigenetic noise landscapes for this cohort by a methylation entropy (ME) method using whole genome bisulfite sequencing (WGBS). Although a universal increase in global ME occurred with chronological age in general control samples, this trend was suppressed in LLIs. Importantly, we identified 38,923 genomic regions with LLI-specific lower ME (LLI-specific lower entropy regions, for short, LLI-specific LERs). These regions were overrepresented in promoters, which likely function in transcriptional noise suppression. Genes associated with LLI-specific LERs have a considerable impact on SNP-based heritability of some aging-related disorders (e.g., asthma and stroke). Furthermore, neutrophil was identified as the primary cell type sustaining LLI-specific LERs. Our results highlight the stability of epigenetic order in promoters of genes involved with aging and age-related disorders within LLI epigenomes. This unique epigenetic feature reveals a previously unknown role of epigenetic order maintenance in specific genomic regions of LLIs, which helps open a new avenue on the epigenetic regulation mechanism in human healthy aging and longevity.

Keywords:  DNA methylation; aging; entropy; epigenetic noise; longevity; long‐lived individuals

DOI:  https://doi.org/10.1111/acel.14163
Proc Nutr Soc. 2024 Apr 01. 1-33

Understanding Age-Related Changes: Exploring the Interplay of Protein Intake, Physical Activity, and Appetite in the Ageing Population.

Dilara Dericioglu, Lisa Methven, Miriam E Clegg.

  Globally, we are currently facing a rapid demographic shift leading to an increase in proportion of older adults within the population. This raises concerns about the potential increase in age-related diseases and their impact on our ability to provide adequate health and end-of-life care. To apply appropriate interventions, understanding the changes that happen with ageing becomes essential. Ageing is often accompanied by a decrease in appetite and physical activity, which may lead to malnutrition, resulting in decreased muscle mass, physical capabilities, and independence. To preserve muscle mass, older adults are advised to increase protein intake and physical activity. However, protein's high satiating effect may cause reduced energy intake. Physical activity is also advised to maintain or enhance older adult's appetite. This review paper aims to discuss appetite-related changes that occur with ageing and their consequences. In particular, it will focus on investigating the relationship between protein intake, physical activity, and their impact on appetite and energy intake in the ageing population. Recent studies suggest that physical activity might contribute to maintaining or enhancing appetite in older adults. Nevertheless, establishing a definitive consensus on the satiating effect of protein in ageing remains a work in progress, despite some promising results in the existing literature.

Keywords:  Ageing; appetite; food intake; older adults; physical activity; protein

DOI:  https://doi.org/10.1017/S0029665124002192
J Comp Physiol B. 2024 Mar 30.

Cell proliferation and regeneration in the gill : By.

Michael G Jonz.

  Seminal studies from the early 20th century defined the structural changes associated with development and regeneration of the gills in goldfish at the gross morphological and cellular levels using standard techniques of light and electron microscopy. More recently, investigations using cell lineage tracing, molecular biology, immunohistochemistry and single-cell RNA-sequencing have pushed the field forward and have begun to reveal the cellular and molecular processes that orchestrate cell proliferation and regeneration in the gills. The gill is a multifunctional organ that mediates an array of important physiological functions, including respiration, ion regulation and excretion of waste products. It is comprised of unique cell types, such as pavement cells, ionocytes, chemoreceptors and undifferentiated stem or progenitor cells that regulate growth and replenish cell populations. The gills develop from the embryonic endoderm and are rich in cell types derived from the neural crest. The gills have the capacity to remodel themselves in response to environmental change, such as in the case of ionocytes, chemoreceptors and the interlamellar cell mass, and can completely regenerate gill filaments and lamellae. Both processes of remodeling and regeneration invariably involve cell proliferation. Although gill regeneration has been reported in only a limited number of fish species, the process appears to have many similarities to regeneration of other organs in fish and amphibians. The present article reviews the studies that have described gill development and growth, and that demonstrate a suite of genes, transcription factors and other proteins involved in cell proliferation and regeneration in the gills.

Keywords:  Fish; Gill; Neural crest; Proliferation; Regeneration; Zebrafish

DOI:  https://doi.org/10.1007/s00360-024-01548-2
Cureus. 2024 Mar;16(3): e55495

Harnessing Genetics to Extend Lifespan and Healthspan: Current Progress and Future Directions.

Paa Kwesi Ankrah, Enock D Mensah, Kwabena Dabie, Caleb Mensah, Benjamin Akangbe, Jonathan Essuman.

  Aging is inevitable, but the lifespan (duration of life) and healthspan (healthy aging) vary greatly among individuals and across species. Unlocking the secrets behind these differences has captivated scientific curiosity for ages. This review presents relevant recent advances in genetics and cell biology that are shedding new light by untangling how subtle changes in conserved genes, pathways, and epigenetic factors influence organismal senescence and associated declines. Biogerontology is a complex and rapidly growing field aimed at elucidating genetic modifications that extend lifespan and healthspan. This review explores gerontogenes, genes influencing lifespan and healthspan across species. Though subtle differences exist, long-lived individuals such as centenarians demonstrate extended healthspans, and numerous studies confirm the heritability of longevity/healthspan genes. Importantly, genes and gerontogenes are directly and indirectly involved in DNA repair, insulin/IGF-1 and mTOR signaling pathways, long non-coding RNAs, sirtuins, and heat shock proteins. The complex interactions between genetics and epigenetics are teased apart. While more research into optimizing healthspan is needed, conserved gerontogenes offer synergistic potential to forestall aging and age-related diseases. Understanding complex longevity genetics brings closer the goal of extending not only lifespan but quality years of life. The primary aim of human Biogerontology is to enhance lifespan and healthspan, but the question remains: are current genetic modifications effectively promoting healthy aging? This article collates the advancements in gerontogenes that enhance lifespan and improve healthspan alongside their potential challenges.

Keywords:  gerontogenes; gerontology; healthspan; lifespan; longevity

DOI:  https://doi.org/10.7759/cureus.55495
Cell Commun Signal. 2024 Apr 03. 22(1): 214

Tobacco smoke condensate-induced senescence in endothelial cells was ameliorated by colchicine treatment via suppression of NF-κB and MAPKs P38 and ERK pathways activation.

Dilaware Khan, Huakang Zhou, Jinliang You, Vera Annika Kaiser, Rajiv K Khajuria, Sajjad Muhammad.

  Smoking is the major cause of cardiovascular diseases and cancer. It induces oxidative stress, leading to DNA damage and cellular senescence. Senescent cells increase the expression and release of pro-inflammatory molecules and matrix metalloproteinase, which are known to play a vital role in the initiation and progression of cardiovascular diseases and metastasis in cancer. The current study investigated the smoking induced cellular senescence and employed colchicine that blocked senescence in endothelial cells exposed to tobacco smoke condensate. Colchicine prevented oxidative stress and DNA damage in tobacco smoke-condensate-treated endothelial cells. Colchicin reduced β-gal activity, improved Lamin B1, and attenuated cell growth arrest markers P21 and P53. Colchicine also ameliorated the expression of SASP factors and inhibited the activation of NF-kB and MAPKs P38 and ERK. In summary, colchicine inhibited tobacco smoke condensate-induced senescence in endothelial cells by blocking the activation of NF-kB and MAPKs P38 and ERK.

Keywords:  HUVECs; MAPKs; NF-kB; SASP factors; Senescence; Tobacco smoke

DOI:  https://doi.org/10.1186/s12964-024-01594-x
Int J Surg. 2024 Apr 04.

Pancreatic cancer: new approaches to drug therapy.

Vincent J Picozzi.

Outcomes in pancreatic ductal adenocarcinoma (PDAC) remain poor due to a variety of biological, clinical, and societal factors. However, in recent years, PDAC has seen 1) increased precision of initial evaluation, 2) increased emphasis on supportive care, 3) deeper understanding of the translation biology of PDAC, especially as pertains to genomic alterations, and 4) foundational combination chemotherapy clinical trials across all disease stages. These advances have led to a wide range of new approaches to drug therapy for PDAC. Currently available drugs are showing added benefit, both by resequencing them with each other and also with respect to other therapeutic modalities. Molecular strategies are being developed to predict response to known therapeutic agents and to identify others. Additionally, a wide range of new drugs for PDAC are under development, including drugs which inhibit critical molecular pathways, drugs which attempt to capitalize on homologous repair deficiencies, immunotherapeutic approaches, antimetabolic agents, and drugs which attack the extracellular matrix which supports PDAC growth. These new approaches offer the promise of improved survival for future PDAC patients.

DOI: https://doi.org/10.1097/JS9.0000000000000877
Yakugaku Zasshi. 2024 ;144(4): 419-429

[Is Biological Aging a Treatable Disease? A Consideration Based on Proposed Mechanisms of Aging].

Sataro Goto.

  In view of the current claim by many researchers that biological aging is a treatable disease, the possibility is discussed whether the claim is realistic, based on several proposed mechanisms of aging. The definition of biological aging is stated referring to physiological aging and pathological aging, since biological aging must be defined for the discussion of whether it can be cured. Aging in animal model is compared with that in humans in terms of common age-associated phenotypes. Major proposed mechanisms of aging are next examined including Genome Instability Theory of aging, Free Radical or Oxidative Stress Theory of Aging, Mitochondrial Theory of Aging, Error Catastrophe Theory of Aging/Translational Error Theory of Aging, Altered Protein Theory of Aging/Proteostasis Theory of Aging, and Epigenetic Theory of Aging. Finally, we discuss whether treatment of aging as a disease is realistic in comparison with possible lifespan extension by retardation of biological aging.

Keywords:  age-associated physiological decline; biological aging definition; biological aging mechanism; geriatric disease

DOI:  https://doi.org/10.1248/yakushi.23-00165-5
Front Cell Dev Biol. 2024 ;12 1359585

ECM and epithelial stem cells: the scaffold of destiny.

Soline Estrach, Charles-Maxime Vivier, Chloé C Féral.

  Adult stem cells play a critical role in maintaining tissue homeostasis and promoting longevity. The intricate organization and presence of common markers among adult epithelial stem cells in the intestine, lung, and skin serve as hallmarks of these cells. The specific location pattern of these cells within their respective organs highlights the significance of the niche in which they reside. The extracellular matrix (ECM) not only provides physical support but also acts as a reservoir for various biochemical and biophysical signals. We will consider differences in proliferation, repair, and regenerative capacities of the three epithelia and review how environmental cues emerging from the niche regulate cell fate. These cues are transduced via mechanosignaling, regulating gene expression, and bring us to the concept of the fate scaffold. Understanding both the analogies and discrepancies in the mechanisms that govern stem cell fate in various organs can offer valuable insights for rejuvenation therapy and tissue engineering.

Keywords:  ECM; adult epithelial stem cells; aging; mechanosignaling; stemness

DOI:  https://doi.org/10.3389/fcell.2024.1359585
Signal Transduct Target Ther. 2024 Apr 03. 9(1): 78

Adeno-associated virus as a delivery vector for gene therapy of human diseases.

Jiang-Hui Wang, Dominic J Gessler, Wei Zhan, Thomas L Gallagher, Guangping Gao.

Adeno-associated virus (AAV) has emerged as a pivotal delivery tool in clinical gene therapy owing to its minimal pathogenicity and ability to establish long-term gene expression in different tissues. Recombinant AAV (rAAV) has been engineered for enhanced specificity and developed as a tool for treating various diseases. However, as rAAV is being more widely used as a therapy, the increased demand has created challenges for the existing manufacturing methods. Seven rAAV-based gene therapy products have received regulatory approval, but there continue to be concerns about safely using high-dose viral therapies in humans, including immune responses and adverse effects such as genotoxicity, hepatotoxicity, thrombotic microangiopathy, and neurotoxicity. In this review, we explore AAV biology with an emphasis on current vector engineering strategies and manufacturing technologies. We discuss how rAAVs are being employed in ongoing clinical trials for ocular, neurological, metabolic, hematological, neuromuscular, and cardiovascular diseases as well as cancers. We outline immune responses triggered by rAAV, address associated side effects, and discuss strategies to mitigate these reactions. We hope that discussing recent advancements and current challenges in the field will be a helpful guide for researchers and clinicians navigating the ever-evolving landscape of rAAV-based gene therapy.

DOI: https://doi.org/10.1038/s41392-024-01780-w