bims-caglex Biomed News
on Cellular aging and life extension
Issue of 2024–09–15
76 papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño
  1. Bazi Bushen mitigates age-related muscular atrophy by alleviating cellular senescence of skeletal muscle.
  2. Identification of a new human senescent skin cell marker ribonucleoside-diphosphate reductase subunit M2 B.
  3. Genetic and Epigenetic Interactions Involved in Senescence of Stem Cells.
  4. Seno-antigen-pulsed dendritic cell vaccine induce anti-aging immunity to improve adipose tissue senescence and metabolic abnormalities.
  5. Exploring the potential of epigenetic clocks in aging research.
  6. In vivo neuron-specific expression of C. elegans reprogramming factor orthologs does not alleviate age-related cognitive decline.
  7. Mitochondrial RNA cytosolic leakage drives the SASP.
  8. Systematic transcriptomic analysis and temporal modelling of human fibroblast senescence.
  9. Reproductive aging weakens offspring survival and constrains the telomerase response to herpesvirus in Pacific oysters.
  10. The Role of Molecular and Cellular Aging Pathways on Age-Related Hearing Loss.
  11. Aged bone marrow macrophages drive systemic aging and age-related dysfunction via extracellular vesicle-mediated induction of paracrine senescence.
  12. Improved health by combining dietary restriction and promoting muscle growth in DNA repair-deficient progeroid mice.
  13. c-Jun N-terminal kinase signaling in aging.
  14. Warmer environmental temperature accelerates aging in mosquitoes, decreasing longevity and worsening infection outcomes.
  15. The cell rejuvenation atlas: leveraging network biology to identify master regulators of rejuvenation strategies.
  16. Adipose tissue senescence: biological changes, hallmarks and therapeutic approaches.
  17. Comparative single-cell transcriptomic analysis across tissues of aging primates reveals specific autologous activation of ZNF281 to mitigate oxidative stress in cornea.
  18. Anti-Inflammatory Role of the Klotho Protein and Relevance to Aging.
  19. Isopropyl 3-(3,4-Dihydroxyphenyl)-2-hydroxypropanoate Alleviates Palmitic Acid-Induced Vascular Aging in HUVEC Cells through ROS/Ferroptosis Pathway.
  20. An anti-aging vaccine: BCG turns back the clock on remyelination failure.
  21. Ovarian tissue autotransplantation improves longevity in mice.
  22. Life in the fastlane? A comparative analysis of gene expression profiles across annual, semi-annual, and non-annual killifishes (Cyprinodontiformes: Nothobranchiidae).
  23. Review on Ginseng and its Potential Active Substance G-Rg2 Against Age-Related Diseases: Traditional Efficacy and Mechanism.
  24. Inhibition of Sirtuin Deacylase Activity by Peroxynitrite.
  25. RNA-DNA hybrids on protein coding genes are stabilized by loss of RNase H and are associated with DNA damages during S-phase in fission yeast.
  26. Tree Longevity: Multifaceted Genetic Strategies and Beyond.
  27. The Multifaceted Role of Endothelial Sirt1 in Vascular Aging: An Update.
  28. Promotion of DNA end resection by BRCA1-BARD1 in homologous recombination.
  29. CO2 protects cells from iron-Fenton oxidative DNA damage in E. coli and humans.
  30. Extracellular vesicle-encapsulated miR-30c-5p reduces aging-related liver fibrosis.
  31. Identification of Cellular Isoschaftoside-Mediated Anti-Senescence Mechanism in RAC2 and LINC00294.
  32. Coffee consumption, cancer, and healthy aging: epidemiological evidence and underlying mechanisms.
  33. Inflammasome components as new therapeutic targets in inflammatory disease.
  34. In vivo liver targeted genome editing as therapeutic approach: progresses and challenges.
  35. Characterization of age-associated inflammasome activation reveals tissue specific differences in transcriptional and post-translational inflammatory responses.
  36. HIV-1 Vpr-induced DNA damage activates NF-κB through ATM-NEMO independent of cell cycle arrest.
  37. Secreted Particle Information Transfer (SPIT) - A Cellular Platform for In Vivo Genetic Engineering.
  38. Sarcopenia in the era of precision health: Towards personalized interventions for healthy longevity.
  39. Pause Patrol: Negative Elongation Factor's role in Promoter-Proximal Pausing and beyond.
  40. Integrating precision health with multidomain interventions to advance strategies for healthy aging.
  41. Independent and joint role of inflammatory diet and physical activity with cognitive function in aging: Evidence from a population-based survey.
  42. Cell cycle re-entry in the aging Drosophila brain.
  43. Mitigating the effects of time in the heart and liver: the variable effects of short- and long-term caloric restriction.
  44. Common DNA sequence variation influences epigenetic aging in African populations.
  45. CARM1 phosphorylation at S595 by p38γ MAPK drives ROS-mediated cellular senescence.
  46. Histone variant H2A.Z is needed for efficient transcription-coupled NER and genome integrity in UV challenged yeast cells.
  47. Hydrogen gas improves proliferation and mitochondrial activity of human adipose-derived stem cells after cryopreservation.
  48. Exploring the Geroprotective Potential of Nutraceuticals.
  49. Prediction of Multiple Degenerative Diseases Based on DNA Methylation in a Co-Physiology Mechanisms Perspective.
  50. Curcumin Inhibits TORC1 and Prolongs the Lifespan of Cells with Mitochondrial Dysfunction.
  51. Microbially mediated phenolic catabolites exert differential genoprotective activities in normal and adenocarcinoma cell lines.
  52. A simple "mix-and-detection" method based on template-free amplification for sensitive measurement of human cellular FEN1.
  53. The Effects of Fisetin on Reducing Biological Aging: A Pilot Study.
  54. Variational inference of single cell time series.
  55. TEX264 drives selective autophagy of DNA lesions to promote DNA repair and cell survival.
  56. MOF-mediated acetylation of CDK9 promotes global transcription by modulating P-TEFb complex formation.
  57. Nuclear actin is a critical regulator of Drosophila female germline stem cell maintenance.
  58. Advances in CRISPR/Cas systems-based cell and gene therapy.
  59. Enhanced pharmacological activities of AKR1C3-activated prodrug AST-3424 in cancer cells with defective DNA repair.
  60. The influence of AHR on immune and tissue biology.
  61. Reconstruction of a robust bacterial replication module.
  62. Podocyte senescence: from molecular mechanisms to therapeutics.
  63. Hyperactivating EZH2 to augment H3K27me3 levels in regulatory T cells enhances immune suppression by driving early effector differentiation.
  64. Cellular processing of beneficial de novo emerging proteins.
  65. Targeted partial reprogramming of age-associated cell states improves markers of health in mouse models of aging.
  66. The opposite aging effect to single cell transcriptome profile among cell subsets.
  67. Histone H3 mutations and their impact on genome stability maintenance.
  68. Hunt for longevity drugs gets new life.
  69. RNA Modifications Shape Hematopoietic Stem Cell Aging: Beyond the Code.
  70. Targeting Fatty Acid Metabolism Abrogates the Differentiation Blockade in Pre-leukemic Cells.
  71. Impaired Incorporation of Fibronectin into the Extracellular Matrix during Aging Exacerbates the Senescent State of Dermal Cells.
  72. MicroRNA-142 regulates gut associated lymphoid tissues and group 3 innate lymphoid cells.
  73. Role of Noncoding RNAs in Modulating Microglial Phenotype.
  74. Disruption of perinatal myeloid niches impacts the aging clock of pancreatic β cells.
  75. SRSF2 is essential for maintaining pancreatic beta-cell identity and regulating glucose homeostasis in mice.
  76. Methylation of KSHV vCyclin by PRMT5 contributes to cell cycle progression and cell proliferation.
  1. J Tradit Complement Med. 2024 Sep;14(5): 510-521
    Bazi Bushen mitigates age-related muscular atrophy by alleviating cellular senescence of skeletal muscle.
    Kunxu Niu, Liping Chang, Runtao Zhang, Yuning Jiang, Xiaogang Shen, Xuan Lu, Shixiong Zhang, Kun Ma, Zhiqin Zhao, Mengnan Li, Yunlong Hou, Yiling Wu.
       Background and aim: Muscular atrophy is one of the most common age-related conditions characterized by the deterioration of skeletal muscle structures and impaired functions. It is associated with cellular senescence and chronic inflammation, which impair the function of muscle stem cells. Bazi Bushen (BZBS) is a patent compound Chinese medicine that has been shown to have anti-aging effects in various animal models. In this study, we investigated the effects and mechanisms of BZBS on muscular atrophy in naturally aged mice.
    Experimental procedure: A muscular atrophy model of naturally aged mice (18 months) was employed with administration of BZBS (2 g/kg/d, 1 g/kg/d) and nicotinamide mononucleotide (NMN, 200 mg/kg/d). After six months of drug administration, muscle weight loss, muscle function and muscle histopathology were measured to evaluate the therapeutic effect of BZBS. The expression of cellular senescence, inflammatory and satellite cell-related factors were used to assess the effects of BZBS in inhibiting cellular senescence, reducing inflammation and improving muscle atrophy.
    Results and conclusion: Compared with age matched natural aging mice, we found that BZBS improved muscle strength, mass, and morphology by reducing senescent cells, inflammatory cytokines, and intermyofiber fibrosis in aged muscle tissues. We also found that BZBS prevented the reduction of Pax7 positive stem cells and stimulated the activation and differentiation into myocytes. Our results suggest that BZBS might be a promising intervention in senile muscular atrophy.
    Keywords:  Bazi Bushen; Cellular senescence; Inflammation; Muscular atrophy; Satellite cell
    DOI:  https://doi.org/10.1016/j.jtcme.2024.01.009
  2. Biogerontology. 2024 Sep 11.
    Identification of a new human senescent skin cell marker ribonucleoside-diphosphate reductase subunit M2 B.
    Kento Takaya, Kazuo Kishi.
      In skin aging, it has been hypothesized that aging fibroblasts accumulate within the epidermal basal layer, dermis, and subcutaneous fat, causing abnormal tissue remodeling and extracellular matrix dysfunction, thereby inducing an aging-related secretory phenotype (SASP). A new treatment for skin aging involves the specific elimination of senescent skin cells, especially fibroblasts within the dermis and keratinocytes in the basal layer. This requires the identification of specific protein markers of senescent cells, such as ribonucleoside-diphosphate reductase subunit M2 B (RRM2B), which is upregulated in various malignancies in response to DNA stress damage. However, the behavior and role of RRM2B in skin aging remain unclear. Therefore, we examined whether RRM2B functions as a senescence marker using a human dermal fibroblast model of aging. In a model of cellular senescence induced by replicative aging and exposure to ionizing radiation or UVB, RRM2B was upregulated at the gene and protein levels. This was correlated with decreased uptake of the senescence-associated β-galactosidase activity and proliferation marker bromodeoxyuridine. RRM2B upregulation was concurrent with the increased expression of SASP factor genes. Furthermore, using fluorescence flow cytometry, RRM2B-positive cells were recovered more frequently in the aging cell population. In aging human skin, RRM2B was also found to be more abundant in the dermis and epidermal basal layer than other proteins. Therefore, RRM2B may serve as a clinical marker to identify senescent skin cells.
    Keywords:  Fibroblast; Keratinocyte; Ribonucleoside-diphosphate reductase subunit M2 B; Senolysis; Skin aging
    DOI:  https://doi.org/10.1007/s10522-024-10135-5
  3. Int J Mol Sci. 2024 Sep 07. pii: 9708. [Epub ahead of print]25(17):
    Genetic and Epigenetic Interactions Involved in Senescence of Stem Cells.
    Florin Iordache, Adriana Cornelia Ionescu Petcu, Diana Mihaela Alexandru.
      Cellular senescence is a permanent condition of cell cycle arrest caused by a progressive shortening of telomeres defined as replicative senescence. Stem cells may also undergo an accelerated senescence response known as premature senescence, distinct from telomere shortening, as a response to different stress agents. Various treatment protocols have been developed based on epigenetic changes in cells throughout senescence, using different drugs and antioxidants, senolytic vaccines, or the reprogramming of somatic senescent cells using Yamanaka factors. Even with all the recent advancements, it is still unknown how different epigenetic modifications interact with genetic profiles and how other factors such as microbiota physiological conditions, psychological states, and diet influence the interaction between genetic and epigenetic pathways. The aim of this review is to highlight the new epigenetic modifications that are involved in stem cell senescence. Here, we review recent senescence-related epigenetic alterations such as DNA methylation, chromatin remodeling, histone modification, RNA modification, and non-coding RNA regulation outlining new possible targets for the therapy of aging-related diseases. The advantages and disadvantages of the animal models used in the study of cellular senescence are also briefly presented.
    Keywords:  acetylation; cellular senescence; epigenetics; histone; methylation; stem cells
    DOI:  https://doi.org/10.3390/ijms25179708
  4. Biomed Pharmacother. 2024 Sep 10. pii: S0753-3322(24)01318-0. [Epub ahead of print]179 117433
    Seno-antigen-pulsed dendritic cell vaccine induce anti-aging immunity to improve adipose tissue senescence and metabolic abnormalities.
    Yin Cao, Xiaoxue Du, Jiahong Yu, Ying Wang, Xinliang Jin, Baijian Gu, Qiliang Yin.
      Anti-aging immunity induced by vaccines was recently reported to enable the elimination of senescent cells. However, the initial immune response to vaccination declines with age, and there is evidence that elderly dendritic cells (DCs) have a reduced capacity to stimulate T cells. Identification of alternative anti-aging vaccine is therefore warranted. Here, we developed a DC vaccine that delivers a cationic protein (CP) fused with the seno-antigen peptides Gpnmb (Gpnmb-CP) into DCs. The Gpnmb-CP-pulsed DC vaccine (Gpnmb-CP-DC) efficiently presented antigens and activated CD8+ T cells, leading to enhanced immune cytotoxicity and memory responses in CD8+ T cells. Thus, the targeted anti-aging immunity triggered by Gpnmb-CP-DC has the ability to selectively eliminate senescent adipocytes and effectively improve age-related metabolic abnormalities in both high-fat diet (HFD)-induced young and aged mice models, as well as in natural aging mouse model. In contrast, the Gpnmb-CP protein vaccine exhibits minimal efficacy in aged mice model. Furthermore, we observed a decreased phagocytic capacity for antigens in aging DCs, accompanied by an upregulation of the immune checkpoint PDL1 expression and a noticeable decline in activated CD8+ T cell. Hence, Gpnmb-CP-DC emerges as a promising vaccine candidate, demonstrating the capacity to induce potent anti-aging immunity, mitigating adipose tissue senescence and metabolic abnormalities, while resilient to the senescent environment of the organism.
    Keywords:  Dendritic cell vaccine; Metabolic abnormalities; Senescence; Seno-antigen
    DOI:  https://doi.org/10.1016/j.biopha.2024.117433
  5. Methods. 2024 Sep 07. pii: S1046-2023(24)00191-9. [Epub ahead of print]
    Exploring the potential of epigenetic clocks in aging research.
    Yuduo Hao, Kaiyuan Han, Ting Wang, Junwen Yu, Hui Ding, Fuying Dao.
      The process of aging is a notable risk factor for numerous age-related illnesses. Hence, a reliable technique for evaluating biological age or the pace of aging is crucial for understanding the aging process and its influence on the progression of disease. Epigenetic alterations are recognized as a prominent biomarker of aging, and epigenetic clocks formulated on this basis have been shown to provide precise estimations of chronological age. Extensive research has validated the effectiveness of epigenetic clocks in determining aging rates, identifying risk factors for aging, evaluating the impact of anti-aging interventions, and predicting the emergence of age-related diseases. This review provides a detailed overview of the theoretical principles underlying the development of epigenetic clocks and their utility in aging research. Furthermore, it explores the existing obstacles and possibilities linked to epigenetic clocks and proposes potential avenues for future studies in this field.
    Keywords:  Aging; Biological age; Epigenetic age; Epigenetic age acceleration; Epigenetic clock
    DOI:  https://doi.org/10.1016/j.ymeth.2024.09.001
  6. MicroPubl Biol. 2024 ;2024
    In vivo neuron-specific expression of C. elegans reprogramming factor orthologs does not alleviate age-related cognitive decline.
    Erik Toraason, Rachel Kaletsky, Coleen Murphy.
      Overexpression of the OSK(M) (Oct4, Sox2, Klf4, with or without cMyc) pluripotency factors have shown promise in rejuvenating the function of aged neurons. To test whether this intervention could also ameliorate age-associated cognitive decline, we used a doxycycline inducible system to overexpress the C. elegans OSK orthologs specifically in aging C. elegans neurons. We find that OSK does not improve short-term associative memory or extend lifespan and can further disrupt chemotaxis behavior. Taken together, our data suggest that OSK-mediated partial reprogramming may have deleterious effects on post-mitotic neurons that function in cognitive processes.
    DOI:  https://doi.org/10.17912/micropub.biology.001304
  7. Res Sq. 2024 Aug 27. pii: rs.3.rs-4876596. [Epub ahead of print]
    Mitochondrial RNA cytosolic leakage drives the SASP.
    Stella Victorelli, Madeline Eppard, Seung-Hwa Woo, Stacia Everts, Helene Martini, Nicholas Pirius, Ana Catarina Franco, Yeaeun Han, Dominik Saul, Patrick Splinter, Steven O'Hara, Lucia Valenzuela-Pérez, Hyun Se Kim Lee, Diana Jurk, Nicholas LaRusso, Petra Hirsova, Joao Passos.
      Senescent cells secrete proinflammatory factors known as the senescence-associated secretory phenotype (SASP), contributing to tissue dysfunction and aging. Mitochondrial dysfunction is a key feature of senescence, influencing SASP via mitochondrial DNA (mtDNA) release and cGAS/STING pathway activation. Here, we demonstrate that mitochondrial RNA (mtRNA) also accumulates in the cytosol of senescent cells, activating RNA sensors RIG-I and MDA5, leading to MAVS aggregation and SASP induction. Inhibition of these RNA sensors significantly reduces SASP factors. Furthermore, BAX and BAK plays a key role in mtRNA leakage during senescence, and their deletion diminishes SASP expression in vitro and in a mouse model of Metabolic Dysfunction Associated Steatohepatitis (MASH). These findings highlight mtRNA's role in SASP regulation and its potential as a therapeutic target for mitigating age-related inflammation.
    DOI:  https://doi.org/10.21203/rs.3.rs-4876596/v1
  8. Front Aging. 2024 ;5 1448543
    Systematic transcriptomic analysis and temporal modelling of human fibroblast senescence.
    R-L Scanlan, L Pease, H O'Keefe, A Martinez-Guimera, L Rasmussen, J Wordsworth, D Shanley.
      Cellular senescence is a diverse phenotype characterised by permanent cell cycle arrest and an associated secretory phenotype (SASP) which includes inflammatory cytokines. Typically, senescent cells are removed by the immune system, but this process becomes dysregulated with age causing senescent cells to accumulate and induce chronic inflammatory signalling. Identifying senescent cells is challenging due to senescence phenotype heterogeneity, and senotherapy often requires a combinatorial approach. Here we systematically collected 119 transcriptomic datasets related to human fibroblasts, forming an online database describing the relevant variables for each study allowing users to filter for variables and genes of interest. Our own analysis of the database identified 28 genes significantly up- or downregulated across four senescence types (DNA damage induced senescence (DDIS), oncogene induced senescence (OIS), replicative senescence, and bystander induced senescence) compared to proliferating controls. We also found gene expression patterns of conventional senescence markers were highly specific and reliable for different senescence inducers, cell lines, and timepoints. Our comprehensive data supported several observations made in existing studies using single datasets, including stronger p53 signalling in DDIS compared to OIS. However, contrary to some early observations, both p16 and p21 mRNA levels rise quickly, depending on senescence type, and persist for at least 8-11 days. Additionally, little evidence was found to support an initial TGFβ-centric SASP. To support our transcriptomic analysis, we computationally modelled temporal protein changes of select core senescence proteins during DDIS and OIS, as well as perform knockdown interventions. We conclude that while universal biomarkers of senescence are difficult to identify, conventional senescence markers follow predictable profiles and construction of a framework for studying senescence could lead to more reproducible data and understanding of senescence heterogeneity.
    Keywords:  big data; cellular senescence; computational model; fibroblast; temporal profile; transcriptomic
    DOI:  https://doi.org/10.3389/fragi.2024.1448543
  9. Sci Adv. 2024 Sep 13. 10(37): eadq2311
    Reproductive aging weakens offspring survival and constrains the telomerase response to herpesvirus in Pacific oysters.
    Andréaz Dupoué, Hugo Koechlin, Matthias Huber, Pauline Merrien, Jacqueline Le Grand, Charlotte Corporeau, Elodie Fleury, Benoît Bernay, Pierre de Villemereuil, Benjamin Morga, Jérémy Le Luyer.
      Telomere length (TL) is increasingly recognized as a molecular marker that reflects how reproductive aging affects intergenerational transmissions. Here, we investigated the effects of parental age on offspring survival and the regulation of TL by examining the telomere-elongating activity of telomerase in the Pacific oyster. We assessed the classical hallmarks of aging in parents at three age classes (young, middle-aged, and old) and crossbred them using a split-brood design to examine the consequences of the nine maternal-by-paternal age combinations on their offspring. Reproductive aging leads to increased larval mortality and accelerated telomere shortening in spats, rendering them more susceptible to infection by the Ostreid herpesvirus. Viral exposure stimulates telomerase activity, a response that we identified as adaptive, but weakened by parental aging. While telomerase lengthens a spat's telomere, paradoxically, longer individual TL predicts higher mortality in adults. The telomerase-telomere complex appeared as a conservative biomarker for distinguishing survivors and losers upon exposure to polymicrobial diseases.
    DOI:  https://doi.org/10.1126/sciadv.adq2311
  10. Int J Mol Sci. 2024 Sep 07. pii: 9705. [Epub ahead of print]25(17):
    The Role of Molecular and Cellular Aging Pathways on Age-Related Hearing Loss.
    Tuba Ege, Litao Tao, Brian J North.
      Aging, a complex process marked by molecular and cellular changes, inevitably influences tissue and organ homeostasis and leads to an increased onset or progression of many chronic diseases and conditions, one of which is age-related hearing loss (ARHL). ARHL, known as presbycusis, is characterized by the gradual and irreversible decline in auditory sensitivity, accompanied by the loss of auditory sensory cells and neurons, and the decline in auditory processing abilities associated with aging. The extended human lifespan achieved by modern medicine simultaneously exposes a rising prevalence of age-related conditions, with ARHL being one of the most significant. While our understanding of the molecular basis for aging has increased over the past three decades, a further understanding of the interrelationship between the key pathways controlling the aging process and the development of ARHL is needed to identify novel targets for the treatment of AHRL. The dysregulation of molecular pathways (AMPK, mTOR, insulin/IGF-1, and sirtuins) and cellular pathways (senescence, autophagy, and oxidative stress) have been shown to contribute to ARHL. However, the mechanistic basis for these pathways in the initiation and progression of ARHL needs to be clarified. Therefore, understanding how longevity pathways are associated with ARHL will directly influence the development of therapeutic strategies to treat or prevent ARHL. This review explores our current understanding of the molecular and cellular mechanisms of aging and hearing loss and their potential to provide new approaches for early diagnosis, prevention, and treatment of ARHL.
    Keywords:  cochlear aging; hair cells; hearing loss; mitochondrial dysfunction; senescence; sirtuins
    DOI:  https://doi.org/10.3390/ijms25179705
  11. Nat Aging. 2024 Sep 12.
    Aged bone marrow macrophages drive systemic aging and age-related dysfunction via extracellular vesicle-mediated induction of paracrine senescence.
    Jing Hou, Kai-Xuan Chen, Chen He, Xiao-Xiao Li, Mei Huang, Yang-Zi Jiang, Yu-Rui Jiao, Qiao-Ni Xiao, Wen-Zhen He, Ling Liu, Nan-Yu Zou, Min Huang, Jie Wei, Ye Xiao, Mi Yang, Xiang-Hang Luo, Chao Zeng, Guang-Hua Lei, Chang-Jun Li.
      The accumulation and systemic propagation of senescent cells contributes to physiological aging and age-related pathology. However, which cell types are most susceptible to the aged milieu and could be responsible for the propagation of senescence has remained unclear. Here we found that physiologically aged bone marrow monocytes/macrophages (BMMs) propagate senescence to multiple tissues, through extracellular vesicles (EVs), and drive age-associated dysfunction in mice. We identified peroxisome proliferator-activated receptor α (PPARα) as a target of microRNAs within aged BMM-EVs that regulates downstream effects on senescence and age-related dysfunction. Demonstrating therapeutic potential, we report that treatment with the PPARα agonist fenofibrate effectively restores tissue homeostasis in aged mice. Suggesting conservation to humans, in a cohort study of 7,986 participants, we found that fenofibrate use is associated with a reduced risk of age-related chronic disease and higher life expectancy. Together, our findings establish that BMMs can propagate senescence to distant tissues and cause age-related dysfunction, and they provide supportive evidence for fenofibrate to extend healthy lifespan.
    DOI:  https://doi.org/10.1038/s43587-024-00694-0
  12. J Cachexia Sarcopenia Muscle. 2024 Sep 08.
    Improved health by combining dietary restriction and promoting muscle growth in DNA repair-deficient progeroid mice.
    Wilbert P Vermeij, Khalid Alyodawi, Ivar van Galen, Jennie L von der Heide, María B Birkisdóttir, Lisanne J Van't Sant, Rutger A Ozinga, Daphne S J Komninos, Kimberly Smit, Yvonne M A Rijksen, Renata M C Brandt, Sander Barnhoorn, Dick Jaarsma, Sathivel Vaiyapuri, Olli Ritvos, Tobias B Huber, Oliver Kretz, Ketan Patel.
       BACKGROUND: Ageing is a complex multifactorial process, impacting all organs and tissues, with DNA damage accumulation serving as a common underlying cause. To decelerate ageing, various strategies have been applied to model organisms and evaluated for health and lifespan benefits. Dietary restriction (DR, also known as caloric restriction) is a well-established long-term intervention recognized for its universal anti-ageing effects. DR temporarily suppresses growth, and when applied to progeroid DNA repair-deficient mice doubles lifespan with systemic health benefits. Counterintuitively, attenuation of myostatin/activin signalling by soluble activin receptor (sActRIIB), boosts the growth of muscle and, in these animals, prevents muscle wasting, improves kidney functioning, and compresses morbidity.
    METHODS: Here, we investigated a combined approach, applying an anabolic regime (sActRIIB) at the same time as DR to Ercc1Δ/- progeroid mice. Following both single treatments and combined, we monitored global effects on body weight, lifespan and behaviour, and local effects on muscle and tissue weight, muscle morphology and function, and ultrastructural and transcriptomic changes in muscle and kidney.
    RESULTS: Lifespan was mostly influenced by DR (extended from approximately 20 to 40 weeks; P < 0.001), with sActRIIB clearly increasing muscle mass (35-65%) and tetanic force (P < 0.001). The combined regime yielded a stable uniform body weight, but increased compared with DR alone, synergistically improved motor coordination and further delayed the onset and development of balance problems. sActRIIB significantly increased muscle fibre size (P < 0.05) in mice subjected to DR and lowered all signs of muscle damage. Ercc1Δ/- mice showed abnormal neuromuscular junctions. Single interventions by sActRIIB treatment or DR only partially rescued this phenotype, while in the double intervention group, the regularly shaped junctional foldings were maintained. In kidney of Ercc1Δ/- mice, we observed a mild but significant foot process effacement, which was restored by either intervention. Transcriptome analysis also pointed towards reduced levels of DNA damage in muscle and kidney by DR, but not sActRIIB, while these levels retained lower in the double intervention.
    CONCLUSIONS: In muscle, we found synergistic effects of combining sActRIIB with DR, but not in kidney, with an overall better health in the double intervention group. Crucially, the benefits of each single intervention are not lost when administered in combination, but rather strengthened, even when sActRIIB was applied late in life, opening opportunities for translation to human.
    Keywords:  Ageing; Dietary restriction; Kidney; Muscle; Myostatin; Progeria
    DOI:  https://doi.org/10.1002/jcsm.13570
  13. Front Aging Neurosci. 2024 ;16 1453710
    c-Jun N-terminal kinase signaling in aging.
    Yihao Li, Li You, Eugenie Nepovimova, Vojtech Adam, Zbynek Heger, Klaudia Jomova, Marian Valko, Qinghua Wu, Kamil Kuca.
      Aging encompasses a wide array of detrimental effects that compromise physiological functions, elevate the risk of chronic diseases, and impair cognitive abilities. However, the precise underlying mechanisms, particularly the involvement of specific molecular regulatory proteins in the aging process, remain insufficiently understood. Emerging evidence indicates that c-Jun N-terminal kinase (JNK) serves as a potential regulator within the intricate molecular clock governing aging-related processes. JNK demonstrates the ability to diminish telomerase reverse transcriptase activity, elevate β-galactosidase activity, and induce telomere shortening, thereby contributing to immune system aging. Moreover, the circadian rhythm protein is implicated in JNK-mediated aging. Through this comprehensive review, we meticulously elucidate the intricate regulatory mechanisms orchestrated by JNK signaling in aging processes, offering unprecedented molecular insights with significant implications and highlighting potential therapeutic targets. We also explore the translational impact of targeting JNK signaling for interventions aimed at extending healthspan and promoting longevity.
    Keywords:  JNK; aging; longevity; molecular insights; therapeutic targets
    DOI:  https://doi.org/10.3389/fnagi.2024.1453710
  14. Immun Ageing. 2024 Sep 11. 21(1): 61
    Warmer environmental temperature accelerates aging in mosquitoes, decreasing longevity and worsening infection outcomes.
    Jordyn S Barr, Lindsay E Martin, Ann T Tate, Julián F Hillyer.
       BACKGROUND: Most insects are poikilotherms and ectotherms, so their body temperature is predicated by environmental temperature. With climate change, insect body temperature is rising, which affects how insects develop, survive, and respond to infection. Aging also affects insect physiology by deteriorating body condition and weakening immune proficiency via senescence. Aging is usually considered in terms of time, or chronological age, but it can also be conceptualized in terms of body function, or physiological age. We hypothesized that warmer temperature decouples chronological and physiological age in insects by accelerating senescence. To investigate this, we reared the African malaria mosquito, Anopheles gambiae, at 27 °C, 30 °C and 32 °C, and measured survival starting at 1-, 5-, 10- and 15-days of adulthood after no manipulation, injury, or a hemocoelic infection with Escherichia coli or Micrococcus luteus. Then, we measured the intensity of an E. coli infection to determine how the interaction between environmental temperature and aging shapes a mosquito's response to infection.
    RESULTS: We demonstrate that longevity declines when a mosquito is infected with bacteria, mosquitoes have shorter lifespans when the temperature is warmer, older mosquitoes are more likely to die, and warmer temperature marginally accelerates the aging-dependent decline in survival. Furthermore, we discovered that E. coli infection intensity increases when the temperature is warmer and with aging, and that warmer temperature accelerates the aging-dependent increase in infection intensity. Finally, we uncovered that warmer temperature affects both bacterial and mosquito physiology.
    CONCLUSIONS: Warmer environmental temperature accelerates aging in mosquitoes, negatively affecting both longevity and infection outcomes. These findings have implications for how insects will serve as pollinators, agricultural pests, and disease vectors in our warming world.
    Keywords:  Climate Change; Infection Intensity; Insect; Mosquito; Physiology; Senescence; Survival
    DOI:  https://doi.org/10.1186/s12979-024-00465-w
  15. Aging (Albany NY). 2024 Sep 09. null
    The cell rejuvenation atlas: leveraging network biology to identify master regulators of rejuvenation strategies.
    Javier Arcos Hodar, Sascha Jung, Mohamed Soudy, Sybille Barvaux, Antonio Del Sol.
      Current rejuvenation strategies, which range from calorie restriction to in vivo partial reprogramming, only improve a few specific cellular processes. In addition, the molecular mechanisms underlying these approaches are largely unknown, which hinders the design of more holistic cellular rejuvenation strategies. To address this issue, we developed SINGULAR (Single-cell RNA-seq Investigation of Rejuvenation Agents and Longevity), a cell rejuvenation atlas that provides a unified system biology analysis of diverse rejuvenation strategies across multiple organs at single-cell resolution. In particular, we leverage network biology approaches to characterize and compare the effects of each strategy at the level of intracellular signaling, cell-cell communication, and transcriptional regulation. As a result, we identified master regulators orchestrating the rejuvenation response and propose that targeting a combination of them leads to a more holistic improvement of age-dysregulated cellular processes. Thus, the interactive database accompanying SINGULAR is expected to facilitate the future design of synthetic rejuvenation interventions.
    Keywords:  aging; cellular biology; computational biology; database; rejuvenation; scRNA-seq
    DOI:  https://doi.org/10.18632/aging.206105
  16. Mech Ageing Dev. 2024 Sep 10. pii: S0047-6374(24)00088-5. [Epub ahead of print] 111988
    Adipose tissue senescence: biological changes, hallmarks and therapeutic approaches.
    Yajuan Zhang, Yaoyao Jiang, Xiaoyue Yang, Yumei Huang, An Pan, Yunfei Liao.
      Adipose tissue (AT), the largest energy storage reservoir and endocrine organ, plays a crucial role in regulating systemic energy metabolism. As one of the most vulnerable tissues during aging, the plasticity of AT is impaired. With age, AT undergoes redistribution, characterized by expansion of visceral adipose tissue (VAT) and reduction of peripheral subcutaneous adipose tissue (SAT). Additionally, age-related changes in AT include reduced adipogenesis of white adipocytes, decreased proliferation and differentiation capacity of mesenchymal stromal/stem cells (MSCs), diminished thermogenic capacity in brown/beige adipocytes, and dysregulation of immune cells. Specific and sensitive hallmarks enable the monitoring and evaluation of the biological changes associated with aging. In this study, we have innovatively proposed seven characteristic hallmarks of AT senescence, including telomere attrition, epigenetic alterations, genomic instability, mitochondrial dysfunction, disabled macroautophagy, cellular senescence, and chronic inflammation, which are intricately interconnected and mutually regulated. Finally, we discussed anti-aging strategies targeting AT, offering insights into mitigating or delaying metabolic disturbances caused by AT senescence.
    Keywords:  Adipose tissue; Aging; Anti-aging strategies; Hallmarks; Senescence
    DOI:  https://doi.org/10.1016/j.mad.2024.111988
  17. Aging Cell. 2024 Sep 10. e14319
    Comparative single-cell transcriptomic analysis across tissues of aging primates reveals specific autologous activation of ZNF281 to mitigate oxidative stress in cornea.
    Yuhua Xiao, Xu Chen, Zheyao Chen, Wangxuan Dai, Xing Hu, Shuyao Zhang, Jiawei Zhong, Jia Chen, Xu Liu, Lingyi Liang, Youjin Hu.
      Reactive oxygen species (ROS) and oxidative stress accelerate cellular aging, but their impact on different tissues varies. The cornea, known for its robust antioxidant defense systems, is relatively resistant to age-related diseases like cancer. However, the precise mechanisms by which the cornea maintains ROS homeostasis during aging remain unclear. Through comparative single-cell transcriptomic analysis of the cornea and other tissues in young and old nonhuman primates, we identified that a ZNF281 coding transcriptomic program is specifically activated in cornea during aging. Further investigation revealed that ZNF281 forms a positive feedback loop with FOXO3 to sense elevated levels of ROS and mitigate their effects potentially by regulating the mitochondrial respiratory chain and superoxide dismutase (SOD) expression. Importantly, we observed that overexpression of ZNF281 in MSCs prevented cellular senescence. In summary, these findings open up possibilities for understanding tissue-specific aging and developing new therapies targeting ROS damage.
    Keywords:  aging; corneal epithelium; nonhuman primate; reactive oxygen species; single‐cell transcriptomic analysis
    DOI:  https://doi.org/10.1111/acel.14319
  18. Cells. 2024 Aug 24. pii: 1413. [Epub ahead of print]13(17):
    Anti-Inflammatory Role of the Klotho Protein and Relevance to Aging.
    Gérald J Prud'homme, Qinghua Wang.
      The α-Klotho protein (hereafter Klotho) is an obligate coreceptor for fibroblast growth factor 23 (FGF23). It is produced in the kidneys, brain and other sites. Klotho insufficiency causes hyperphosphatemia and other anomalies. Importantly, it is associated with chronic pathologies (often age-related) that have an inflammatory component. This includes atherosclerosis, diabetes and Alzheimer's disease. Its mode of action in these diseases is not well understood, but it inhibits or regulates multiple major pathways. Klotho has a membrane form and a soluble form (s-Klotho). Cytosolic Klotho is postulated but not well characterized. s-Klotho has endocrine properties that are incompletely elucidated. It binds to the FGF receptor 1c (FGFR1c) that is widely expressed (including endothelial cells). It also attaches to soluble FGF23, and FGF23/Klotho binds to FGFRs. Thus, s-Klotho might be a roaming FGF23 coreceptor, but it has other functions. Notably, Klotho (cell-bound or soluble) counteracts inflammation and appears to mitigate related aging (inflammaging). It inhibits NF-κB and the NLRP3 inflammasome. This inflammasome requires priming by NF-κB and produces active IL-1β, membrane pores and cell death (pyroptosis). In accord, Klotho countered inflammation and cell injury induced by toxins, damage-associated molecular patterns (DAMPs), cytokines, and reactive oxygen species (ROS). s-Klotho also blocks the TGF-β receptor and Wnt ligands, which lessens fibrotic disease. Low Klotho is associated with loss of muscle mass (sarcopenia), as occurs in aging and chronic diseases. s-Klotho counters the inhibitory effects of myostatin and TGF-β on muscle, reduces inflammation, and improves muscle repair following injury. The inhibition of TGF-β and other factors may also be protective in diabetic retinopathy and age-related macular degeneration (AMD). This review examines Klotho functions especially as related to inflammation and potential applications.
    Keywords:  Alzheimer; FGF23; Klotho; NF-κB; TGF-β; aging; atherosclerosis; fibrosis; inflammasome; sarcopenia
    DOI:  https://doi.org/10.3390/cells13171413
  19. Int J Mol Sci. 2024 Aug 27. pii: 9278. [Epub ahead of print]25(17):
    Isopropyl 3-(3,4-Dihydroxyphenyl)-2-hydroxypropanoate Alleviates Palmitic Acid-Induced Vascular Aging in HUVEC Cells through ROS/Ferroptosis Pathway.
    Xin He, Xiaohui Zheng, Weidong Xie.
      Vascular aging is an important factor leading to cardiovascular diseases such as hypertension and atherosclerosis. Hyperlipidemia or fat accumulation may play an important role in vascular aging and cardiovascular disease. Isopropyl 3-(3,4-dihydroxyphenyl)-2-hydroxypropanoate (IDHP) has biological activity and can exert cardiovascular protection, which may be related to ferroptosis. However, the exact mechanism remains undefined. We hypothesized that IDHP may have a protective effect on blood vessels by regulating vascular aging caused by hyperlipidemia or vascular wall fat accumulation. The aim of this study is to investigate the protective effect and mechanism of IDHP on palmitic acid-induced human umbilical vein endothelial cells (HUVEC) based on senescence and ferroptosis. We found that IDHP could delay vascular aging, reduce the degree of ferrous ion accumulation and lipid peroxidation, and protect vascular cells from injury. These effects may be achieved by attenuating excessive reactive oxygen species (ROS) and ferroptosis signaling pathways generated in vascular endothelial cells. In short, our study identified IDHP as one of the antioxidant agents to slow down lipotoxicity-induced vascular senescence through the ROS/ferroptosis pathway. IDHP has new medicinal value and provides a new therapeutic idea for delaying vascular aging in patients with dyslipidemia.
    Keywords:  IDHP; ROS; aging; ferroptosis; palmitic acid
    DOI:  https://doi.org/10.3390/ijms25179278
  20. Immunity. 2024 Sep 10. pii: S1074-7613(24)00374-1. [Epub ahead of print]57(9): 2005-2007
    An anti-aging vaccine: BCG turns back the clock on remyelination failure.
    Janssen M Kotah, Bart J L Eggen.
      Aging leads to alterations that precipitate or aggravate several diseases that occur across our lifespan. In the CNS, aging affects the capacity to maintain and repair the myelin sheaths that protect axons and facilitate neuronal signaling. Tiwari et al. report aging-associated transcriptional responses in microglia after demyelination, which could be reversed by epigenetic remodeling after BCG vaccination.
    DOI:  https://doi.org/10.1016/j.immuni.2024.08.001
  21. Front Physiol. 2024 ;15 1443494
    Ovarian tissue autotransplantation improves longevity in mice.
    Nikolai N Ruhliada.
      In this study, we show the improvement in life longevity in an experimental mouse model after step-by-step autologous ovarian transplantation and compare its effects with exogenic transdermal estradiol usage. This has proven to be more efficient than "traditional" hormonal replacement therapy. Despite the high speed and effectiveness of estradiol replacement deficiency in blood by its oral or transdermal use, no significant increase in the life longevity of animals and possibly in women was noted. The function of the transplanted fragment is usually limited to 6-12 months. This is enough for oncofertility purposes, sometimes, but not for longevity improvement. We performed periodical tissue return (autologous transplantation), containing both the cortex and medulla in the experimental mouse model, which resulted in a statistically reliable improvement in longevity. Our experience indicates the important role of medullary ovarian factors in slowing the aging process in the body and increasing the life expectancy in the experiment. As shown, the transdermal estrogen supportive therapy for ovarian deficiency improves estrogen levels but causes much slower decreases in the follicle stimulating hormone (FSH) and luteinizing hormone (LH). Moreover, we attained the best longevity with step-by-step periodic ovarian autotransplantation, thus making "prosthetics" of ovarian function longer than it is preplanned physiologically [direct correlation between the levels of FSH and lifespan (r = 0.98)]. The experimental model we suggested could be projected to other mammals or humans as cortical transplantation provides the same results for reproduction restoration in mice and humans and even for hormone level normalization, but there is still a lack of information about anti-aging factors in the ovarian medulla and cortex. Hence, we consider that the most important factor for the anti-aging ovarian transplantation technology is to preserve and transfer both the medulla and cortex as parts of the whole ovary.
    Keywords:  estradiol; lifespan; longevity; ovaries; transplantation
    DOI:  https://doi.org/10.3389/fphys.2024.1443494
  22. PLoS One. 2024 ;19(9): e0308855
    Life in the fastlane? A comparative analysis of gene expression profiles across annual, semi-annual, and non-annual killifishes (Cyprinodontiformes: Nothobranchiidae).
    Chi Jing Leow, Kyle R Piller.
      The Turquoise Killifish is an important vertebrate for the study of aging and age-related diseases due to its short lifespan. Within Nothobranchiidae, species possess annual, semi-annual, or non-annual life-histories. We took a comparative approach and examined gene expression profiles (QuantSeq) from 62 individuals from eleven nothobranchid species that span three life-histories. Our results show significant differences in differentially expressed genes (DEGs) across life-histories with non-annuals and semi-annuals being most similar, and annuals being the most distinct. At finer scales, we recovered significant differences in DEGs for DNA repair genes and show that non-annual and semi-annuals share similar gene expression profiles, while annuals are distinct. Most of the GO terms enriched in annuals are related to metabolic processes. However, GO terms, including translation, protein transport, and DNA replication initiation also are enriched in annuals. Non-annuals are enriched in Notch signaling pathway genes and downregulated in the canonical Wnt signaling pathway compared to annual species, which suggests that non-annuals have stronger regulation in cellular processes. This study provides support for congruency in DEGs involved in these life-histories and provides strong evidence that a particular set of candidate genes may be worthy of study to investigate their role in the aging process.
    DOI:  https://doi.org/10.1371/journal.pone.0308855
  23. J Ethnopharmacol. 2024 Sep 09. pii: S0378-8741(24)01080-8. [Epub ahead of print] 118781
    Review on Ginseng and its Potential Active Substance G-Rg2 Against Age-Related Diseases: Traditional Efficacy and Mechanism.
    Yu-Zhuo Zhang, De-Yang Huo, Zhi Liu, Xin-Dian Li, Zi Wang, Wei Li.
       ETHNOPHARMACOLOGICAL RELEVANCE: According to the Shen Nong Herbal Classic, Ginseng (Panax ginseng C.A. Meyer) is documented to possess life-prolonging effects and is extensively utilized in traditional Chinese medicine for the treatment of various ailments such as qi deficiency, temper deficiency, insomnia, and forgetfulness. Ginseng is commonly employed for replenishing qi and nourishing blood, fortifying the body and augmenting immunity; it has demonstrated efficacy in alleviating fatigue, enhancing memory, and retarding aging. Furthermore, it exhibits a notable ameliorative impact on age-related conditions including cardiovascular diseases and neurodegenerative disorders. One of its active constituents - ginsenoside Rg2 (G-Rg2) - exhibits potential therapeutic efficacy in addressing these ailments.
    AIM OF THE REVIEW: The aim of this review is to explore the traditional efficacy of ginseng in anti-aging diseases and the modern pharmacological mechanism of its potential active substance G-Rg2, in order to provide strong theoretical support for further elucidating the mechanism of its anti-aging effect.
    METHODS: This review provides a comprehensive analysis of the traditional efficacy of ginseng and the potential mechanisms underlying the anti-age-related disease properties of G-Rg2, based on an extensive literature review up to March 12, 2024, from PubMed, Web of Science, Scopus, Cochrane, and Google Scholar databases. Potential anti-aging mechanisms of G-Rg2 were predicted using network pharmacology and molecular docking analysis techniques.
    RESULTS: In traditional Chinese medicine theory, ginseng has been shown to improve aging-related diseases with a variety of effects, including tonifying qi, strengthening the spleen and stomach, nourishing yin, regulating yin and yang, as well as calming the mind. Its potential active ingredient G-Rg2 has demonstrated significant therapeutic potential in age-related diseases, especially central nervous system and cardiovascular diseases. G-Rg2 exhibited a variety of pharmacological activities, including anti-apoptotic, anti-inflammatory and antioxidant effects. Meanwhile, the network pharmacological analyses and molecular docking results were consistent with the existing literature review, further validating the potential efficacy of G-Rg2 as an anti-aging agent.
    CONCLUSION: The review firstly explores the ameliorative effects of ginseng on a wide range of age-related diseases based on TCM theories. Secondly, the article focuses on the remarkable significance and value demonstrated by G-Rg2 in age-related cardiovascular and neurodegenerative diseases. Consequently, G-Rg2 has broad prospects for development in intervening in aging and treating age-related health problems.
    Keywords:  Anti-aging; Ginseng; Ginsenoside Rg2; Molecular docking; Network pharmacology
    DOI:  https://doi.org/10.1016/j.jep.2024.118781
  24. Biochemistry. 2024 Sep 10.
    Inhibition of Sirtuin Deacylase Activity by Peroxynitrite.
    Kelsey Bohl, Sarah L Wynia-Smith, Rachel A Jones Lipinski, Brian C Smith.
      Sirtuins are a class of enzymes that deacylate protein lysine residues using NAD+ as a cosubstrate. Sirtuin deacylase activity has been historically regarded as protective; loss of sirtuin deacylase activity potentially increases susceptibility to aging-related disease development. However, which factors may inhibit sirtuins during aging or disease is largely unknown. Increased oxidant and inflammatory byproduct production damages cellular proteins. Previously, we and others found that sirtuin deacylase activity is inhibited by the nitric oxide (NO)-derived cysteine post-translational modification S-nitrosation. However, the comparative ability of the NO-derived oxidant peroxynitrite (ONOO-) to affect human sirtuin activity had not yet been assessed under uniform conditions. Here, we compare the ability of ONOO- (donated from SIN-1) to post-translationally modify and inhibit SIRT1, SIRT2, SIRT3, SIRT5, and SIRT6 deacylase activity. In response to SIN-1 treatment, inhibition of SIRT1, SIRT2, SIRT3, SIRT5, and SIRT6 deacylase activity correlated with increased tyrosine nitration. Mass spectrometry identified multiple novel tyrosine nitration sites in SIRT1, SIRT3, SIRT5, and SIRT6. As each sirtuin isoform has at least one tyrosine nitration site within the catalytic core, nitration may result in sirtuin inhibition. ONOO- can also react with cysteine residues, resulting in sulfenylation; however, only SIRT1 showed detectable peroxynitrite-mediated cysteine sulfenylation. While SIRT2, SIRT3, SIRT5, and SIRT6 showed no detectable sulfenylation, SIRT6 likely undergoes transient sulfenylation, quickly resolving into an intermolecular disulfide bond. These results suggest that the aging-related oxidant peroxynitrite can post-translationally modify and inhibit sirtuins, contributing to susceptibility to aging-related disease.
    DOI:  https://doi.org/10.1021/acs.biochem.4c00257
  25. Genes Cells. 2024 Sep 09.
    RNA-DNA hybrids on protein coding genes are stabilized by loss of RNase H and are associated with DNA damages during S-phase in fission yeast.
    Tomoko Sagi, Daichi Sadato, Kazuto Takayasu, Hiroyuki Sasanuma, Yutaka Kanoh, Hisao Masai.
      RNA-DNA hybrid is a part of the R-loop which is an important non-standard nucleic acid structure. RNA-DNA hybrid/R-loop causes genomic instability by inducing DNA damages or inhibiting DNA replication. It also plays biologically important roles in regulation of transcription, replication, recombination and repair. Here, we have employed catalytically inactive human RNase H1 mutant (D145N) to visualize RNA-DNA hybrids and map their genomic locations in fission yeast cells. The RNA-DNA hybrids appear as multiple nuclear foci in rnh1∆rnh201∆ cells lacking cellular RNase H activity, but not in the wild-type. The majority of RNA-DNA hybrid loci are detected at the protein coding regions and tRNA. In rnh1∆rnh201∆ cells, cells with multiple Rad52 foci increase during S-phase and about 20% of the RNA-DNA hybrids overlap with Rad52 loci. During S-phase, more robust association of Rad52 with RNA-DNA hybrids was observed in the protein coding region than in M-phase. These results suggest that persistent RNA-DNA hybrids in the protein coding region in rnh1∆rnh201∆ cells generate DNA damages during S-phase, potentially through collision with DNA replication forks.
    Keywords:  DNA damages; RNA–DNA hybrid; RNase H; Rad52; R‐loop
    DOI:  https://doi.org/10.1111/gtc.13157
  26. Plant Cell Environ. 2024 Sep 10.
    Tree Longevity: Multifaceted Genetic Strategies and Beyond.
    Sian Liu, Huimin Xu, Guibin Wang, Biao Jin, Fuliang Cao, Li Wang.
      Old trees are remarkable for their ability to endure for centuries or even millennia, acting as recordkeepers of historical climate and custodians of genetic diversity. The secret to their longevity has long been a subject of fascination. Despite the challenges associated with studying old trees, such as massive size, slow growth rate, long lifespan and often remote habitat, accumulating studies have investigated the mechanisms underlying tree aging and longevity over the past decade. The recent publication of high-quality genomes of long-lived tree species, coupled with research on stem cell function and secondary metabolites in longevity, has brought us closer to unlocking the secrets of arboreal longevity. This review provides an overview of the global distribution of old trees and examines the environmental and anthropogenic factors that shape their presence. We summarize the contributions of physiological characteristics, stem cell activity, and immune system responses to their extraordinary longevity. We also explore the genetic and epigenetic 'longevity code', which consists of resistance and defense genes, DNA repair genes and patterns of DNA methylation modification. Further, we highlight key areas for future research that could enhance our understanding of the mechanisms underlying tree longevity.
    Keywords:  DNA methylation; R genes; secondary metabolites; stem cells
    DOI:  https://doi.org/10.1111/pce.15146
  27. Cells. 2024 Sep 01. pii: 1469. [Epub ahead of print]13(17):
    The Multifaceted Role of Endothelial Sirt1 in Vascular Aging: An Update.
    Roberto Campagna, Laura Mazzanti, Veronica Pompei, Sonila Alia, Arianna Vignini, Monica Emanuelli.
      NAD+-dependent deacetylase sirtuin-1 (Sirt1) belongs to the sirtuins family, known to be longevity regulators, and exerts a key role in the prevention of vascular aging. By aging, the expression levels of Sirt1 decline with a severe impact on vascular function, such as the rise of endothelial dysfunction, which in turn promotes the development of cardiovascular diseases. In this context, the impact of Sirt1 activity in preventing endothelial senescence is particularly important. Given the key role of Sirt1 in counteracting endothelial senescence, great efforts have been made to deepen the knowledge about the intricate cross-talks and interactions of Sirt1 with other molecules, in order to set up possible strategies to boost Sirt1 activity to prevent or treat vascular aging. The aim of this review is to provide a proper background on the regulation and function of Sirt1 in the vascular endothelium and to discuss the recent advances regarding the therapeutic strategies of targeting Sirt1 to counteract vascular aging.
    Keywords:  Sirt1; Sirtuin 1; endothelial senescence; vascular aging
    DOI:  https://doi.org/10.3390/cells13171469
  28. Nature. 2024 Sep 11.
    Promotion of DNA end resection by BRCA1-BARD1 in homologous recombination.
    Sameer Salunkhe, James M Daley, Hardeep Kaur, Nozomi Tomimatsu, Chaoyou Xue, Vivek B Raina, Angela M Jasper, Cody M Rogers, Wenjing Li, Shuo Zhou, Rahul Mojidra, Youngho Kwon, Qingming Fang, Jae-Hoon Ji, Aida Badamchi Shabestari, O'Taveon Fitzgerald, Hoang Dinh, Bipasha Mukherjee, Amyn A Habib, Robert Hromas, Alexander V Mazin, Elizabeth V Wasmuth, Shaun K Olsen, David S Libich, Daohong Zhou, Weixing Zhao, Eric C Greene, Sandeep Burma, Patrick Sung.
      The licensing step of DNA double-strand break repair by homologous recombination entails resection of DNA ends to generate a single-stranded DNA template for assembly of the repair machinery consisting of the RAD51 recombinase and ancillary factors1. DNA end resection is mechanistically intricate and reliant on the tumour suppressor complex BRCA1-BARD1 (ref. 2). Specifically, three distinct nuclease entities-the 5'-3' exonuclease EXO1 and heterodimeric complexes of the DNA endonuclease DNA2, with either the BLM or WRN helicase-act in synergy to execute the end resection process3. A major question concerns whether BRCA1-BARD1 directly regulates end resection. Here, using highly purified protein factors, we provide evidence that BRCA1-BARD1 physically interacts with EXO1, BLM and WRN. Importantly, with reconstituted biochemical systems and a single-molecule analytical tool, we show that BRCA1-BARD1 upregulates the activity of all three resection pathways. We also demonstrate that BRCA1 and BARD1 harbour stand-alone modules that contribute to the overall functionality of BRCA1-BARD1. Moreover, analysis of a BARD1 mutant impaired in DNA binding shows the importance of this BARD1 attribute in end resection, both in vitro and in cells. Thus, BRCA1-BARD1 enhances the efficiency of all three long-range DNA end resection pathways during homologous recombination in human cells.
    DOI:  https://doi.org/10.1038/s41586-024-07910-2
  29. bioRxiv. 2024 Aug 26. pii: 2024.08.26.609766. [Epub ahead of print]
    CO2 protects cells from iron-Fenton oxidative DNA damage in E. coli and humans.
    Aaron M Fleming, Justin C Dingman, Cynthia J Burrows.
      Whereas hydroxyl radical is commonly named as the Fenton product responsible for DNA and RNA damage in cells, here we demonstrate that the cellular reaction generates carbonate radical anion due to physiological levels of bicarbonate. Analysis of the metabolome, transcriptome and, in human cells, the nuclear genome shows a consistent buffering of H2O2-induced oxidative stress leading to one common pathway, namely guanine oxidation. Particularly revealing are nanopore-based studies of direct RNA sequencing of cytosolic and mitochondrial ribosomal RNA along with glycosylase-dependent qPCR studies of oxidative DNA damage in telomeres. The focusing of oxidative modification on one pathway is consistent with the highly evolved base excision repair suite of enzymes and their involvement in gene regulation in response to oxidative stress.
    DOI:  https://doi.org/10.1101/2024.08.26.609766
  30. Aging Cell. 2024 Sep 13. e14310
    Extracellular vesicle-encapsulated miR-30c-5p reduces aging-related liver fibrosis.
    Alice C Rodrigues, Yujing J Heng, Frank J Slack.
      Aging is associated with decreased health span, and despite the recent advances made in understanding the mechanisms of aging, no antiaging drug has been approved for therapy. Therefore, strategies to promote a healthy life in aging are desirable. Previous work has shown that chronic treatment with extracellular vesicles (EVs) from young mice prolongs lifespan in old mice, but the mechanism of action of this effect on liver metabolism is not known. Here we investigated the role of treatment with EVs derived from young sedentary (EV-C) or exercised (EV-EX) mice in the metabolism of old mice and aimed to identify key youthful-associated microRNA (miRNA) cargos that could promote healthy liver function. We found that aged mice treated with either EV-C or EV-EX had higher insulin sensitivity, higher locomotor activity resulting in longer distance traveled in the cage, and a lower respiratory exchange ratio compared to mice treated with EVs from aged mice (EV-A). In the liver, treatment with young-derived EVs reduced aging-induced liver fibrosis. We identified miR-30c in the EVs as a possible youth-associated miRNA as its level was higher in circulating EVs of young mice. Treatment of aged mice with EVs transfected with miR-30c mimic reduced stellate cell activation in the liver and reduced fibrosis compared to EV-negative control by targeting Foxo3. Our results suggest that by delivering juvenile EVs to old mice, we can improve their liver health. Moreover, we identified miR-30c as a candidate for antiaging liver therapy.
    Keywords:  aging; exercise; extracellular vesicles; fibrosis; miR‐30; microRNAs
    DOI:  https://doi.org/10.1111/acel.14310
  31. Molecules. 2024 Sep 04. pii: 4182. [Epub ahead of print]29(17):
    Identification of Cellular Isoschaftoside-Mediated Anti-Senescence Mechanism in RAC2 and LINC00294.
    Yun Haeng Lee, Byeong Hyeon So, Kyeong Seon Lee, Myeong Uk Kuk, Ji Ho Park, Jee Hee Yoon, Yoo Jin Lee, Du Yeol Kim, Min Seon Kim, Hyung Wook Kwon, Youngjoo Byun, Ki Yong Lee, Joon Tae Park.
      As cellular senescence, reactive oxygen species (ROS) accumulate excessively, causing cellular damage. Flavonoids derived from natural products are known for their antioxidant effects and their ability to delay cellular senescence. Previous studies have attempted to mitigate cellular senescence using flavonoids from natural sources. However, the detailed mechanisms and regulatory targets of some flavonoids exhibiting antioxidant effects have not been fully elucidated. Therefore, we screened a library of flavonoids for antioxidant properties. Isoschaftoside, a glycosidic flavonoid, significantly reduced ROS levels in senescent cells. It was found that mitochondrial function was restored, and dependence on glycolysis was reduced in senescent cells treated with isoschaftoside. Additionally, we identified that isoschaftoside suppresses ROS by reducing the expression of RAC2 and LINC00294 in senescent cells. Taken together, this study establishes a novel mechanism for ROS inhibition and the regulation of cellular senescence by isoschaftoside. Our findings contribute important insights to antioxidant and anti-senescence research.
    Keywords:  flavonoid; isoschaftoside; reactive oxygen species (ROS); senescence amelioration
    DOI:  https://doi.org/10.3390/molecules29174182
  32. Geroscience. 2024 Sep 13.
    Coffee consumption, cancer, and healthy aging: epidemiological evidence and underlying mechanisms.
    Setor K Kunutsor, Andrea Lehoczki, Jari A Laukkanen.
      This comprehensive review examines the role of coffee consumption in promoting healthy aging and its potential impact on cancer prevention. Previous research has shown that moderate coffee intake may contribute to extending healthspan and enhancing longevity through beneficial effects on cardiometabolic health and key biological processes involved in aging. However, the relationship between coffee consumption and cancer risk remains controversial. This review synthesizes longitudinal observational and interventional data on the effects of coffee consumption on overall and site-specific cancers, explores underlying biological mechanisms, and discusses clinical and public health implications. Additionally, the review highlights evidence from Mendelian randomization (MR) studies to assess potential causal relationships. Our findings suggest that coffee consumption is associated with a reduced risk of several cancers, including skin, liver, prostate, and endometrial cancers, and may also lower cancer recurrence rates, particularly in colorectal cancer. These protective associations appear consistent across different demographic groups, with the most significant benefits observed at consumption levels of three or more cups per day. However, evidence is inconclusive for many other cancers, and coffee consumption is consistently linked to an increased risk of lung cancer. MR studies generally do not support a strong causal relationship for most cancers, though some suggest potential protective effects for hepatocellular, colorectal, and possibly prostate cancers, with mixed results for ovarian cancer and an increased risk for esophageal cancer and multiple myeloma. The protective effect of coffee on liver and prostate cancer is supported by both observational and MR studies. The potential anti-cancer benefits of coffee are attributed to its bioactive compounds, such as caffeine, chlorogenic acids, and diterpenes, which possess antioxidant and anti-inflammatory properties. These compounds may reduce oxidative stress, inhibit cancer cell proliferation, induce apoptosis, and modulate hormone levels. The review emphasizes the need for further research to clarify dose-response relationships, causal associations, and the biological mechanisms underlying these associations. While coffee consumption appears to contribute to cancer prevention and healthy aging, caution is warranted due to the increased risk of certain cancers, highlighting the complexity of its health effects.
    Keywords:  Caffeine; Cancer; Coffee consumption; Healthspan; Longevity; Mendelian randomization; Mortality
    DOI:  https://doi.org/10.1007/s11357-024-01332-8
  33. Nat Rev Immunol. 2024 Sep 09.
    Inflammasome components as new therapeutic targets in inflammatory disease.
    Rebecca C Coll, Kate Schroder.
      Inflammation drives pathology in many human diseases for which there are no disease-modifying drugs. Inflammasomes are signalling platforms that can induce pathological inflammation and tissue damage, having potential as an exciting new class of drug targets. Small-molecule inhibitors of the NLRP3 inflammasome that are now in clinical trials have demonstrated proof of concept that inflammasomes are druggable, and so drug development programmes are now focusing on other key inflammasome molecules. In this Review, we describe the potential of inflammasome components as candidate drug targets and the novel inflammasome inhibitors that are being developed. We discuss how the signalling biology of inflammasomes offers mechanistic insights for therapeutic targeting. We also discuss the major scientific and technical challenges associated with drugging these molecules during preclinical development and clinical trials.
    DOI:  https://doi.org/10.1038/s41577-024-01075-9
  34. Front Genome Ed. 2024 ;6 1458037
    In vivo liver targeted genome editing as therapeutic approach: progresses and challenges.
    Chiara Simoni, Elena Barbon, Andrés F Muro, Alessio Cantore.
      The liver is an essential organ of the body that performs several vital functions, including the metabolism of biomolecules, foreign substances, and toxins, and the production of plasma proteins, such as coagulation factors. There are hundreds of genetic disorders affecting liver functions and, for many of them, the only curative option is orthotopic liver transplantation, which nevertheless entails many risks and long-term complications. Some peculiar features of the liver, such as its large blood flow supply and the tolerogenic immune environment, make it an attractive target for in vivo gene therapy approaches. In recent years, several genome-editing tools mainly based on the clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR-Cas9) system have been successfully exploited in the context of liver-directed preclinical or clinical therapeutic applications. These include gene knock-out, knock-in, activation, interference, or base and prime editing approaches. Despite many achievements, important challenges still need to be addressed to broaden clinical applications, such as the optimization of the delivery methods, the improvement of the editing efficiency, and the risk of on-target or off-target unwanted effects and chromosomal rearrangements. In this review, we highlight the latest progress in the development of in vivo liver-targeted genome editing approaches for the treatment of genetic disorders. We describe the technological advancements that are currently under investigation, the challenges to overcome for clinical applicability, and the future perspectives of this technology.
    Keywords:  delivery methods; genome editing; lipid nano particle; liver; liver directed genome editing; viral vectors
    DOI:  https://doi.org/10.3389/fgeed.2024.1458037
  35. Immun Ageing. 2024 Sep 10. 21(1): 60
    Characterization of age-associated inflammasome activation reveals tissue specific differences in transcriptional and post-translational inflammatory responses.
    Sarah Talley, Tyler Nguyen, Lily Van Ye, Rasa Valiauga, Jake DeCarlo, Jabra Mustafa, Benjamin Cook, Fletcher A White, Edward M Campbell.
      Aging is associated with systemic chronic, low-grade inflammation, termed 'inflammaging'. This pattern of inflammation is multifactorial and is driven by numerous inflammatory pathways, including the inflammasome. However, most studies to date have examined changes in the transcriptomes that are associated with aging and inflammaging, despite the fact that inflammasome activation is driven by a series of post-translational activation steps, culminating in the cleavage and activation of caspase-1. Here, we utilized transgenic mice expressing a caspase-1 biosensor to examine age-associated inflammasome activation in various organs and tissues to define these post-translational manifestations of inflammaging. Consistent with other studies, we observe increased inflammation, including inflammasome activation, in aged mice and specific tissues. However, we note that the degree of inflammasome activation is not uniformly associated with transcriptional changes commonly used as a surrogate for inflammasome activation in tissues. Furthermore, we used a skull thinning technique to monitor central nervous system inflammasome activation in vivo in aged mice and found that neuroinflammation is significantly amplified in aged mice in response to endotoxin challenge. Together, these data reveal that inflammaging is associated with both transcriptional and post-translational inflammatory pathways that are not uniform between tissues and establish new methodologies for measuring age-associated inflammasome activation in vivo and ex vivo.
    DOI:  https://doi.org/10.1186/s12979-024-00462-z
  36. mBio. 2024 Sep 13. e0024024
    HIV-1 Vpr-induced DNA damage activates NF-κB through ATM-NEMO independent of cell cycle arrest.
    Carina Sandoval, Karly Nisson, Oliver I Fregoso.
      Lentiviruses encode a number of multi-functional accessory proteins, however, the primary role of the accessory protein Vpr remains unclear. As Vpr engages the host DNA damage response (DDR) at multiple steps, modulation of the DDR is considered central to the function(s) of Vpr. Vpr activates ataxia telangiectasia and Rad3 (ATR)-mediated DDR signaling, resulting in cell cycle arrest. However, the cellular consequences of Vpr-induced DNA damage, and the connection of Vpr-induced DNA damage to other Vpr functions, are unknown. Here, we determined that HIV-1 Vpr-induced DNA damage activates the ATM-NF-κB essential modulator (NEMO) pathway and alters cellular transcription via NF-κB/RelA. Through RNA-sequencing (RNA-seq) of cells expressing Vpr or mutants that separate the ability of Vpr to induce DNA damage from other DDR phenotypes, we identified that Vpr alters the transcriptome independent of cell cycle arrest. In tissue-cultured U2OS cells and primary human monocyte-derived macrophages (MDMs), we showed Vpr activates both ataxia telangiectasia mutated (ATM) and NF-κB/RelA signaling cascades. While inhibition of NEMO did not affect Vpr-induced DNA damage, it prevented NF-κB activation by Vpr, highlighting the importance of NEMO in Vpr-mediated transcriptional reprogramming. Virion-delivered Vpr was sufficient to induce DNA damage and activate ATM-NEMO dependent NF-κB transcription, suggesting that engagement of the DDR and transcriptional changes can occur early during viral replication. Together, our data uncover cellular consequences of Vpr-induced DNA damage and provide a mechanism for how Vpr activates NF-κB through DNA damage and ATM-NEMO signaling, which occur independent of cell cycle arrest. We propose this is essential to overcoming restrictive environments, such as in macrophages, to enhance viral replication.IMPORTANCEThe HIV accessory protein Vpr is multi-functional and required for viral replication in vivo, yet how Vpr enhances viral replication is unknown. Emerging literature suggests that a conserved function of Vpr is the engagement of the host DNA damage response (DDR). For example, Vpr activates DDR signaling, causes DDR-dependent cell cycle arrest, promotes degradation of various DDR proteins, and alters cellular consequences of DDR activation. However, a central understanding of how these phenotypes connect and how they affect HIV-infected cells remains unknown. Here, we found that Vpr-induced DNA damage alters the host transcriptome by activating an essential transcription pathway, NF-κB. This occurs early during the infection of primary human immune cells, suggesting NF-κB activation and transcriptome remodeling are important for establishing productive HIV-1 infection. Together, our study provides novel insights into how Vpr alters the host environment through the DDR, and what roles Vpr and the DDR play to enhance HIV replication.
    Keywords:  DNA damage; NF-kB; Vpr; host response; human immunodeficiency virus; macrophages; transcription factors; virus-host interactions
    DOI:  https://doi.org/10.1128/mbio.00240-24
  37. Res Sq. 2024 Aug 30. pii: rs.3.rs-4810212. [Epub ahead of print]
    Secreted Particle Information Transfer (SPIT) - A Cellular Platform for In Vivo Genetic Engineering.
    Hiromitsu Nakauchi, Carsten Charlesworth, Shota Homma, Fabian Suchy, Sicong Wang, Joydeep Bhadhury, Anais Amaya, Joab Camarena, Jinyu Zhang, Tze Tan, Kyomi Igarashi.
      A multitude of tools now exist that allow us to precisely manipulate the human genome in a myriad of different ways. However, successful delivery of these tools to the cells of human patients remains a major barrier to their clinical implementation. Here we introduce a new cellular approach for in vivo genetic engineering, Secreted Particle Information Transfer (SPIT) that utilizes human cells as delivery vectors for in vivo genetic engineering. We demonstrate the application of SPIT for cell-cell delivery of Cre recombinase and CRISPR-Cas9 enzymes, we show that genetic logic can be incorporated into SPIT and present the first demonstration of human cells as a delivery platform for in vivo genetic engineering in immunocompetent mice. We successfully applied SPIT to genetically modify multiple organs and tissue stem cells in vivo including the liver, spleen, intestines, peripheral blood, and bone marrow. We anticipate that by harnessing the large packaging capacity of a human cell's nucleus, the ability of human cells to engraft into patients' long term and the capacity of human cells for complex genetic programming, that SPIT will become a paradigm shifting approach for in vivo genetic engineering.
    DOI:  https://doi.org/10.21203/rs.3.rs-4810212/v1
  38. J Chin Med Assoc. 2024 Sep 10.
    Sarcopenia in the era of precision health: Towards personalized interventions for healthy longevity.
    Liang-Kung Chen.
      Sarcopenia, characterized by the progressive loss of skeletal muscle mass and function, significantly impacts health outcomes in older adults. This review explores the evolving landscape of sarcopenia research, with a particular focus on its unique characteristics in Asian populations and emerging pharmaceutical interventions. Recent studies have revealed distinct patterns of muscle mass decline in Asian adults, particularly in women, challenging the universal application of global sarcopenia diagnostic criteria. The Asian Working Group for Sarcopenia has proposed region-specific diagnostic criteria, acknowledging these ethnic variations. Prevalence estimates of sarcopenia vary widely, ranging from 10% to 40% in community-dwelling older adults. For specific chronic conditions, the prevalence of sarcopenia is notably higher, reaching 35% for cardiovascular diseases and 24.5% for chronic kidney disease. Sarcopenia is strongly associated with various chronic conditions, increasing the risk of falls by 1.5-3 times and significantly increasing mortality risk by 29-51%. Current management strategies primarily involve resistance exercise and nutritional interventions, with a recommended daily protein intake of at least 1.2 g/kg to maintain muscle health. Pharmaceutical development has gained significant momentum, with over 20 compounds in various stages of clinical trials. These include myostatin inhibitors, selective androgen receptor modulators, ghrelin receptor agonists, mesenchymal stem cell therapy and follistatin gene therapy. However, the unique dietary patterns, cultural contexts, and potentially distinct drug responses in Asian populations necessitate tailored interventions and Asia-specific clinical trials. Future directions include refining Asian-specific diagnostic criteria, conducting large-scale epidemiological studies across multiple Asian countries, developing culturally appropriate interventions, integrating sarcopenia management into chronic disease care, and advancing pharmaceutical research with a focus on Asian populations. In conclusion, sarcopenia emerges as a critical nexus in the aging process, intricately linked with multiple organ systems and chronic conditions, underscoring the imperative for its recognition as a cornerstone in person-centered care and the holistic management of age-related health challenges.
    DOI:  https://doi.org/10.1097/JCMA.0000000000001164
  39. J Mol Biol. 2024 Sep 04. pii: S0022-2836(24)00399-1. [Epub ahead of print] 168779
    Pause Patrol: Negative Elongation Factor's role in Promoter-Proximal Pausing and beyond.
    Annette J Diao, Bonnie G Su, Seychelle M Vos.
      RNA polymerase (Pol) II is highly regulated to ensure appropriate gene expression. Early transcription elongation is associated with transient pausing of RNA Pol II in the promoter-proximal region. In multicellular organisms, this pausing is stabilized by the association of transcription elongation factors DRB-sensitivity inducing factor (DSIF) and Negative Elongation Factor (NELF). DSIF is a broadly conserved transcription elongation factor whereas NELF is mostly restricted to the metazoan lineage. Mounting evidence suggests that NELF association with RNA Pol II serves as checkpoint for either release into rapid and productive transcription elongation or premature termination at promoter-proximal pause sites. Here we summarize NELF's roles in promoter-proximal pausing, transcription termination, DNA repair, and signaling based on decades of cell biological, biochemical, and structural work and describe areas for future research.
    DOI:  https://doi.org/10.1016/j.jmb.2024.168779
  40. J Nutr Health Aging. 2024 Sep 05. pii: S1279-7707(24)00441-X. [Epub ahead of print]28(10): 100354
    Integrating precision health with multidomain interventions to advance strategies for healthy aging.
    Liang-Kung Chen.
      
    Keywords:  Digital health; Frailty; Healthy aging; Intrinsic capacity; Multidomain interventions; Precision health
    DOI:  https://doi.org/10.1016/j.jnha.2024.100354
  41. Gen Hosp Psychiatry. 2024 Sep 08. pii: S0163-8343(24)00192-0. [Epub ahead of print]91 52-59
    Independent and joint role of inflammatory diet and physical activity with cognitive function in aging: Evidence from a population-based survey.
    Litao Du, Ting Li, Xiangli Xue, Qiang He, Yang Pan, Si Chen, Xianliang Zhang.
       OBJECTIVE: This study aims to explore the independent and joint association of physical activity (PA) and inflammatory diet with cognitive function in aging.
    METHOD: Data from the 2011-2014 National Health and Nutrition Examination Survey (NHANES) was used. 2249 NHANES participants with valid data represented a weighted population of 50.5 million American residents aged 60 and older. This study separately analyzed the independent associations of PA (measured by global physical activity questionnaire) and inflammatory diet (measured by energy-adjusted dietary inflammatory index from 24-h dietary recall), and their joints (inactive & pro-inflammatory as reference) with cognitive function (assessed by three cognitive tests), and considered an individual of different status and non-linear effect by sub-group and restricted cubic splines (RCS) analysis, respectively. All analysis was multivariable-adjusted and sample-weighted.
    RESULTS: The results showed that inflammatory diet was independently associated with lower cognitive function, with a 1.08, 1.29, 2.67, 0.56 lower score in the Registry for Alzheimer's Disease word list learning test (CERAD), the Animal Fluency Test (AFT), the Digit Symbol Substitution test (DSST), Z-scores, and 51 %, 62 %, 63 %, 93 % higher odds ratio (OR) of lower performance in CERAD, AFT, DSST, and p-MCI, respectively. PA was independently associated with higher cognitive function, with a 1.41, 3.37, and 0.52 higher score in AFT, DSST, Z-scores, and 28 %, 51 %, 41 % lower ORs of lower performance in CERAD and DSST and p-MCI, respectively. Active & Anti-inflammatory was always positively associated with cognitive function, with a 1.42, 2.69, 5.47, and 1.04 higher score for CERAD, AFT, DSST, and Z-score, a 58 %, 56 %, 74 %, 76 % lower ORs of lower performance in CERAT, AFT, DSST, and p-MCI, respectively, which elicited the maximum compared to other joints.
    CONCLUSION: Adhering to both active PA and anti-inflammatory diet is recommended for cognitive management in older adults. Sticking to either active PA or anti-inflammatory diet also shows potential cognitive benefits, with the diet possibly playing more vital role.
    Keywords:  Cognitive function; Diet; Inflammatory diet; Joint association; Physical activity
    DOI:  https://doi.org/10.1016/j.genhosppsych.2024.09.003
  42. bioRxiv. 2024 Aug 26. pii: 2024.08.26.609689. [Epub ahead of print]
    Cell cycle re-entry in the aging Drosophila brain.
    Deena Damschroder, Jenny Sun, Katherine O McDonald, Laura Buttitta.
      The brain is an organ comprised mostly of long-lived, quiescent cells that perform vital functions throughout an animal's life. Due to the brain's limited regenerative ability, these long-lived cells must engage unique mechanisms to cope with accumulated damage over time. We have shown that a subset of differentiated neuronal and glial cells in the fruit fly brain become polyploid during adulthood. Cell cycle re-entry in the brain has previously been associated with neurodegeneration, but there may be a more complex relationship between polyploidy and cell fitness in the brain. Here, we examine how known lifespan modifiers influence the accumulation of polyploidy in the aging fly brain. Flies aged at a low temperature, or with a low protein diet, accumulate polyploid cells in the brain more slowly than expected if this phenotype were solely regulated by lifespan mechanisms. Despite the slower accumulation of polyploid cells, animals under conditions that extend lifespan eventually reach similar levels of polyploidy in the brain as controls. Our work suggests known lifespan modifiers can influence the timing of cell cycle re-entry in the adult brain, indicating there is a flexible window of cell cycle plasticity in the aging brain.
    DOI:  https://doi.org/10.1101/2024.08.26.609689
  43. Mech Ageing Dev. 2024 Sep 11. pii: S0047-6374(24)00092-7. [Epub ahead of print] 111992
    Mitigating the effects of time in the heart and liver: the variable effects of short- and long-term caloric restriction.
    Milica Prvulovic, Sladjan Pavlovic, Slavica Borkovic Mitic, Valentina Simeunovic, Andjela Vukojevic, Smilja Todorovic, Aleksandra Mladenovic.
      Caloric restriction (CR) is known for its anti-aging benefits, partly due to reduced oxidative stress and enhanced antioxidant defense. However, CR outcomes vary based on its intensity, timing, and duration. This study explored CR's effects on antioxidant activity in the heart and liver of male Wistar rats during aging. We investigated two CR paradigms: long-term CR (LTCR), started early in life, and short-term CR (STCR), initiated in middle or old age for 3 months. Contrary to previous findings of short-term CR deleterious effects of on the nervous system, our results revealed increased levels of key antioxidants after STCR. More specifically, we found an increase in GSH-Px and GSH under STCR that was particularly pronounced in the liver, while an increase in CAT and GR activities was observed in the heart of the STCR groups. Catalase was characterized as an enzyme particularly responsive to CR, as its activity was also increased in both the liver and heart after long-term caloric restriction. Our results highlight a significant tissue-specific response to CR and contribute to our understanding of the dynamic effects of CR, which in turn has implications for refining its therapeutic potential in combating age-related decline.
    Keywords:  aging; antioxidants; caloric restriction; heart; liver; oxidative stress
    DOI:  https://doi.org/10.1016/j.mad.2024.111992
  44. bioRxiv. 2024 Aug 26. pii: 2024.08.26.608843. [Epub ahead of print]
    Common DNA sequence variation influences epigenetic aging in African populations.
    Gillian L Meeks, Brooke Scelza, Hana M Asnake, Sean Prall, Etienne Patin, Alain Froment, Maud Fagny, Lluis Quintana-Murci, Brenna M Henn, Shyamalika Gopalan.
      Aging is associated with genome-wide changes in DNA methylation in humans, facilitating the development of epigenetic age prediction models. However, most of these models have been trained primarily on European-ancestry individuals, and none account for the impact of methylation quantitative trait loci (meQTL). To address these gaps, we analyzed the relationships between age, genotype, and CpG methylation in 3 understudied populations: central African Baka (n = 35), southern African ‡Khomani San (n = 52), and southern African Himba (n = 51). We find that published prediction methods yield higher mean errors in these cohorts compared to European-ancestry individuals, and find that unaccounted-for DNA sequence variation may be a significant factor underlying this loss of accuracy. We leverage information about the associations between DNA genotype and CpG methylation to develop an age predictor that is minimally influenced by meQTL, and show that this model remains accurate across a broad range of genetic backgrounds. Intriguingly, we also find that the older individuals and those exhibiting relatively lower epigenetic age acceleration in our cohorts tend to carry more epigenetic age-reducing genetic variants, suggesting a novel mechanism by which heritable factors can influence longevity.
    DOI:  https://doi.org/10.1101/2024.08.26.608843
  45. Redox Biol. 2024 Sep 06. pii: S2213-2317(24)00322-7. [Epub ahead of print]76 103344
    CARM1 phosphorylation at S595 by p38γ MAPK drives ROS-mediated cellular senescence.
    Yena Cho, Yong Kee Kim.
      CARM1 is predominantly localized in the nucleus and plays a pivotal role in maintaining mitochondrial homeostasis by regulating gene expression. It suppresses mitochondrial biogenesis by downregulating PGC-1α and TFAM expression, while promoting mitochondrial fission through increased DNM1L expression. Under oxidative stress, CARM1 translocates to the cytoplasm, where it directly methylates DRP1 and accelerates mitochondrial fission, enhancing reactive oxygen species (ROS) production. Cytoplasmic localization of CARM1 is facilitated by its phosphorylation at S595 by ROS-activated p38γ MAPK, creating a positive feedback loop. Consequently, cytoplasmic CARM1 contributes to cellular senescence by altering mitochondrial dynamics and increasing ROS levels. This observation was supported by the increased cytoplasmic CARM1 levels and disrupted mitochondrial dynamics in the transformed 10T1/2 cells. Moreover, CARM1 inhibitors not only inhibit the proliferation of cancer cells but also induce apoptotic death in senescent cells. These findings highlight the potential of CARM1 inhibitors, particularly those targeting cytoplasmic functions, as novel strategies for eliminating cancer and senescent cells.
    Keywords:  CARM1; Mitochondrial homeostasis; ROS; Senescence; p38γ MAPK
    DOI:  https://doi.org/10.1016/j.redox.2024.103344
  46. PLoS Genet. 2024 Sep 10. 20(9): e1011300
    Histone variant H2A.Z is needed for efficient transcription-coupled NER and genome integrity in UV challenged yeast cells.
    Hélène Gaillard, Toni Ciudad, Andrés Aguilera, Ralf E Wellinger.
      The genome of living cells is constantly challenged by DNA lesions that interfere with cellular processes such as transcription and replication. A manifold of mechanisms act in concert to ensure adequate DNA repair, gene expression, and genome stability. Bulky DNA lesions, such as those induced by UV light or the DNA-damaging agent 4-nitroquinoline oxide, act as transcriptional and replicational roadblocks and thus represent a major threat to cell metabolism. When located on the transcribed strand of active genes, these lesions are handled by transcription-coupled nucleotide excision repair (TC-NER), a yet incompletely understood NER sub-pathway. Here, using a genetic screen in the yeast Saccharomyces cerevisiae, we identified histone variant H2A.Z as an important component to safeguard transcription and DNA integrity following UV irradiation. In the absence of H2A.Z, repair by TC-NER is severely impaired and RNA polymerase II clearance reduced, leading to an increase in double-strand breaks. Thus, H2A.Z is needed for proficient TC-NER and plays a major role in the maintenance of genome stability upon UV irradiation.
    DOI:  https://doi.org/10.1371/journal.pgen.1011300
  47. Regen Ther. 2024 Jun;26 571-577
    Hydrogen gas improves proliferation and mitochondrial activity of human adipose-derived stem cells after cryopreservation.
    Koji Kimura, Yasuhiko Tabata.
      The objective of this study is to evaluate the effect of hydrogen gas on the biological functions of human adipose-derived stem cells (hADSC) in cryopreservation. hADSC were cryopreserved by a commercial cell preservation solution in the presence of hydrogen gas. After cryopreservation at -80 °C, the viability, initial attachment morphology, and biological parameters of cells cryopreserved were evaluated to compare with those of cells cryopreserved in the absence of hydrogen gas. The hydrogen concentration in the cell preservation solution was 2.0 ppm immediately after preparation and after that decreased with time. The presence of hydrogen gas permitted cells to significantly increase the proliferation of cells in addition to the percent initial adhesion. The number of cells in the spread state was significantly high compared with that of hydrogen gas-free cryopreserved cells. The cell cycle measurement with the flow cytometry and measurement of intracellular reactive oxygen species (ROS) were performed to demonstrate an enhanced cell cycle and a decreased ROS production. In the cell cycle assay, the percentage of cells in the mitotic phase increased. The presence of hydrogen gas decreased hydroxyl radicals immediately to a significantly great extent after thawing. It is concluded that the presence of hydrogen gas during cryopreservation is promising to improve the biological behavior of cells after cell thawing in terms of cells viability, proliferation or metabolic activity.
    Keywords:  Cell cryopreservation; Cell proliferation; Hydrogen gas; Mitochondrial activity; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.reth.2024.08.004
  48. Nutrients. 2024 Aug 24. pii: 2835. [Epub ahead of print]16(17):
    Exploring the Geroprotective Potential of Nutraceuticals.
    Nadia Alejandra Rivero-Segura, Emmanuel Alejandro Zepeda-Arzate, Selma Karime Castillo-Vazquez, Patrick Fleischmann-delaParra, Jessica Hernández-Pineda, Edgar Flores-Soto, Paola García-delaTorre, Edgar Antonio Estrella-Parra, Juan Carlos Gomez-Verjan.
      Aging is the result of the accumulation of a wide variety of molecular and cellular damages over time, meaning that "the more damage we accumulate, the higher the possibility to develop age-related diseases". Therefore, to reduce the incidence of such diseases and improve human health, it becomes important to find ways to combat such damage. In this sense, geroprotectors have been suggested as molecules that could slow down or prevent age-related diseases. On the other hand, nutraceuticals are another set of compounds that align with the need to prevent diseases and promote health since they are biologically active molecules (occurring naturally in food) that, apart from having a nutritional role, have preventive properties, such as antioxidant, anti-inflammatory and antitumoral, just to mention a few. Therefore, in the present review using the specialized databases Scopus and PubMed we collected information from articles published from 2010 to 2023 in order to describe the role of nutraceuticals during the aging process and, given their role in targeting the hallmarks of aging, we suggest that they are potential geroprotectors that could be consumed as part of our regular diet or administered additionally as nutritional supplements.
    Keywords:  aging; bioactive compounds; geroprotectors; hallmarks of aging; nutraceuticals
    DOI:  https://doi.org/10.3390/nu16172835
  49. Int J Mol Sci. 2024 Sep 01. pii: 9514. [Epub ahead of print]25(17):
    Prediction of Multiple Degenerative Diseases Based on DNA Methylation in a Co-Physiology Mechanisms Perspective.
    Li Zhang, Ruirui Cai, Chencai Wang, Jialong Liu, Zhejun Kuang, Han Wang.
      Degenerative diseases oftentimes occur within the continuous process of aging, and the corresponding clinical manifestations may be neurodegeneration, neoplastic diseases, or various human complex diseases. DNA methylation provides the opportunity to explore aging and degenerative diseases as epigenetic traits. It has already been applied to age prediction and disease diagnosis. It has been shown that various degenerative diseases share co-physiology mechanisms with each other, clues of which may be gained from studying the aging process. Here, we endeavor to predict the risk of degenerative diseases in an aging-relevant comorbid mechanism perspective. Firstly, an epigenetic clock method was implemented based on a multi-scale convolutional neural network, and a Shapley feature attribution analysis was applied to discover the aging-related CpG sites. Then, these sites were further screened to a smaller subset composed of 196 sites by using biomics analysis according to their biological functions and mechanisms. Finally, we constructed a multilayer perceptron (MLP)-based degenerative disease risk prediction model, Mlp-DDR, which was well trained and tested to accurately classify nine degenerative diseases. Recent studies also suggest that DNA methylation plays a significant role in conditions like osteoporosis and osteoarthritis, broadening the potential applications of our model. This approach significantly advances the ability to understand degenerative diseases and represents a substantial shift from traditional diagnostic methods. Despite the promising results, limitations regarding model complexity and dataset diversity suggest directions for future research, including the development of tissue-specific epigenetic clocks and the inclusion of a wider range of diseases.
    Keywords:  DNA methylation; deep learning; degenerative diseases; epigenetic clock
    DOI:  https://doi.org/10.3390/ijms25179514
  50. Cells. 2024 Sep 01. pii: 1470. [Epub ahead of print]13(17):
    Curcumin Inhibits TORC1 and Prolongs the Lifespan of Cells with Mitochondrial Dysfunction.
    Arshia Naaz, Yizhong Zhang, Nashrul Afiq Faidzinn, Sonia Yogasundaram, Rajkumar Dorajoo, Mohammad Alfatah.
      Aging is an inevitable biological process that contributes to the onset of age-related diseases, often as a result of mitochondrial dysfunction. Understanding the mechanisms behind aging is crucial for developing therapeutic interventions. This study investigates the effects of curcumin on postmitotic cellular lifespan (PoMiCL) during chronological aging in yeast, a widely used model for human postmitotic cellular aging. Our findings reveal that curcumin significantly prolongs the PoMiCL of wildtype yeast cells, with the most pronounced effects observed at lower concentrations, indicating a hormetic response. Importantly, curcumin also extends the lifespan of postmitotic cells with mitochondrial deficiencies, although the hormetic effect is absent in these defective cells. Mechanistically, curcumin inhibits TORC1 activity, enhances ATP levels, and induces oxidative stress. These results suggest that curcumin has the potential to modulate aging and offer therapeutic insights into age-related diseases, highlighting the importance of context in its effects.
    Keywords:  TORC1; aging; curcumin; lifespan; mitochondria; postmitotic cells; yeast
    DOI:  https://doi.org/10.3390/cells13171470
  51. Int J Food Sci Nutr. 2024 Sep 11. 1-14
    Microbially mediated phenolic catabolites exert differential genoprotective activities in normal and adenocarcinoma cell lines.
    Brian Óg Murphy, Cheryl Latimer, Sara Dobani, L Kirsty Pourshahidi, Massimilano Fontana, Nigel G Ternan, Gordon McDougall, Ian Rowland, Gema Pereira-Caro, Kieran M Tuohy, Daniele Del Rio, Tahani M Almutairi, Alan Crozier, Nenad Naumovski, Chris I R Gill.
      Age-associated decline of nuclear factor erythroid 2-related factor 2 (Nrf2) activity and DNA repair efficiency leads to the accumulation of DNA damage and increased risk of cancer. Understanding the mechanisms behind increased levels of damaged DNA is crucial for developing interventions to mitigate age-related cancer risk. Associated with various health benefits, (poly)phenols and their microbially mediated phenolic catabolites represent a potential means to reduce DNA damage. Four colonic-microbiota-derived phenolic catabolites were investigated for their ability to reduce H2O2-induced oxidative DNA damage and modulate the Nrf2-Antixoidant Response Element (ARE) pathway, in normal (CCD 841 CoN) and adenocarcinoma (HT29) colonocyte cell lines. Each catabolite demonstrated significant (p < .001) genoprotective activity and modulation of key genes in the Nrf2-ARE pathway. Overall, the colon-derived phenolic metabolites, when assessed at physiologically relevant concentrations, reduced DNA damage in both normal and adenocarcinoma colonic cells in response to oxidative challenge, mediated in part via upregulation of the Nrf2-ARE pathway.
    Keywords:  3-(3′-hydroxyphenyl)propanoic acid; 3-(phenyl)propanoic acid; 4-hydroxybenzoic acid; Benzoic acid; COMET assay; colonic cells
    DOI:  https://doi.org/10.1080/09637486.2024.2397055
  52. Talanta. 2024 Sep 10. pii: S0039-9140(24)01242-6. [Epub ahead of print]281 126863
    A simple "mix-and-detection" method based on template-free amplification for sensitive measurement of human cellular FEN1.
    Yue-Ying Li, Su Jiang, Ting-Ting Pan, Yanbo Wang, Chun-Yang Zhang.
      Flap endonuclease 1 (FEN1) is a structure-specific nuclease that can specially identify and cleave 5' flap of branched duplex DNA, and it plays a critical role in DNA metabolic pathways and human diseases. Herein, we propose a simple "mix-and-detection" strategy for sensitive measurement of human cellular FEN1 on basis of template-free amplification. We design a dumbbell probe with 5' flap as a substrate of FEN1 and a NH2-labeled 3' termini to prevent nonspecific amplification. When FEN1 is present, the 5' flap is cleaved to release a free 3'-OH termini, initiating Ribonuclease HII (RNase HII)-assisted terminal deoxynucleotidyl transferase (TdT)-induced amplification for the production of a significant fluorescence signal. Due to the high exactitude of TdT-mediated extension reaction and RNase HII-induced single ribonucleotide excise, this assay shows excellent specificity and high sensitivity with a detection limit of 5.64 × 10-6 U/μL. Importantly, it can detect intracellular FEN1 activity with single-cell sensitivity under isothermal condition in a "mix-and-detection" manner, screen the FEN1 inhibitors, and even discriminate tumor cells from normal cells, offering a new platform for disease diagnosis and drug discovery.
    Keywords:  Disease diagnosis; Dumbbell probe; Flap endonuclease 1; Mix-and-detection; Template-free amplification
    DOI:  https://doi.org/10.1016/j.talanta.2024.126863
  53. Altern Ther Health Med. 2024 Sep 13. pii: AT11358. [Epub ahead of print]
    The Effects of Fisetin on Reducing Biological Aging: A Pilot Study.
    Edwin Lee, Morgan Burns.
      Fisetin, a natural flavonoid compound, is a senolytic agent that has shown promise in extending the lifespan of aging mice. Our goal was to determine whether Fisetin can reduce human biological aging, as verified by the TruAge test. This would be the first study in healthy human adults over the age of 50 years old to determine if Fisetin can reduce their biological age. Fisetin 500 mg daily was administered for one week per month for six months. The results showed that four out of ten healthy adults experienced a reduction in biological aging, five out of ten saw an increase, and one out of ten had no change. No adverse effects were noted among the ten subjects. Telomere lengths did not statistically change with the use of Fisetin. Because five of ten had an increase in biological age, taking Fisetin as an anti- aging agent is not recommended until more extensive studies are done.
  54. bioRxiv. 2024 Aug 30. pii: 2024.08.29.610389. [Epub ahead of print]
    Variational inference of single cell time series.
    Bingxian Xu, Rosemary Braun.
      Time course single-cell RNA sequencing (scRNA-seq) enables researchers to probe genome-wide expression dynamics at the the single cell scale. However, when gene expression is affected jointly by time and cellular identity, analyzing such data - including conducting cell type annotation and modeling cell type-dependent dynamics - becomes challenging. To address this problem, we propose SNOW (SiNgle cell flOW map), a deep learning algorithm to deconvolve single cell time series data into time- dependent and time-independent contributions. SNOW has a number of advantages. First, it enables cell type annotation based on the time-independent dimensions. Second, it yields a probabilistic model that can be used to discriminate between biological temporal variation and batch effects contaminating individual timepoints, and provides an approach to mitigate batch effects. Finally, it is capable of projecting cells forward and backward in time, yielding time series at the individual cell level. This enables gene expression dynamics to be studied without the need for clustering or pseudobulking, which can be error prone and result in information loss. We describe our probabilistic framework in detail and demonstrate SNOW using data from three distinct time course scRNA-seq studies. Our results show that SNOW is able to construct biologically meaningful latent spaces, remove batch effects, and generate realistic time-series at the single-cell level. By way of example, we illustrate how the latter may be used to enhance the detection of cell type-specific circadian gene expression rhythms, and may be readily extended to other time-series analyses.
    DOI:  https://doi.org/10.1101/2024.08.29.610389
  55. Cell. 2024 Sep 05. pii: S0092-8674(24)00911-5. [Epub ahead of print]
    TEX264 drives selective autophagy of DNA lesions to promote DNA repair and cell survival.
    Pauline Lascaux, Gwendoline Hoslett, Sara Tribble, Camilla Trugenberger, Ivan Antičević, Cecile Otten, Ignacio Torrecilla, Stelios Koukouravas, Yichen Zhao, Hongbin Yang, Ftoon Aljarbou, Annamaria Ruggiano, Wei Song, Cristiano Peron, Giulio Deangeli, Enric Domingo, James Bancroft, Loïc Carrique, Errin Johnson, Iolanda Vendrell, Roman Fischer, Alvin Wei Tian Ng, Joanne Ngeow, Vincenzo D'Angiolella, Nuno Raimundo, Tim Maughan, Marta Popović, Ira Milošević, Kristijan Ramadan.
      DNA repair and autophagy are distinct biological processes vital for cell survival. Although autophagy helps maintain genome stability, there is no evidence of its direct role in the repair of DNA lesions. We discovered that lysosomes process topoisomerase 1 cleavage complexes (TOP1cc) DNA lesions in vertebrates. Selective degradation of TOP1cc by autophagy directs DNA damage repair and cell survival at clinically relevant doses of topoisomerase 1 inhibitors. TOP1cc are exported from the nucleus to lysosomes through a transient alteration of the nuclear envelope and independent of the proteasome. Mechanistically, the autophagy receptor TEX264 acts as a TOP1cc sensor at DNA replication forks, triggering TOP1cc processing by the p97 ATPase and mediating the delivery of TOP1cc to lysosomes in an MRE11-nuclease- and ATR-kinase-dependent manner. We found an evolutionarily conserved role for selective autophagy in DNA repair that enables cell survival, protects genome stability, and is clinically relevant for colorectal cancer patients.
    Keywords:  DNA repair; DNA replication; TEX264; colorectal cancer; genome stability; nucleophagy; protein degradation; selective autophagy; topoisomerase 1 cleavage complex; zebrafish
    DOI:  https://doi.org/10.1016/j.cell.2024.08.020
  56. FEBS J. 2024 Sep 09.
    MOF-mediated acetylation of CDK9 promotes global transcription by modulating P-TEFb complex formation.
    Wenqi Chen, Jinmeng Chu, Yujuan Miao, Wenwen Jiang, Fei Wang, Na Zhang, Jingji Jin, Yong Cai.
      Cyclin-dependent kinase 9 (CDK9), a catalytic subunit of the positive transcription elongation factor b (P-TEFb) complex, is a global transcriptional elongation factor associated with cell proliferation. CDK9 activity is regulated by certain histone acetyltransferases, such as p300, GCN5 and P/CAF. However, the impact of males absent on the first (MOF) (also known as KAT8 or MYST1) on CDK9 activity has not been reported. Therefore, the present study aimed to elucidate the regulatory role of MOF on CDK9. We present evidence from systematic biochemical assays and molecular biology approaches arguing that MOF interacts with and acetylates CDK9 at the lysine 35 (i.e. K35) site, and that this acetyl-group can be removed by histone deacetylase HDAC1. Notably, MOF-mediated acetylation of CDK9 at K35 promotes the formation of the P-TEFb complex through stabilizing CDK9 protein and enhancing its association with cyclin T1, which further increases RNA polymerase II serine 2 residues levels and global transcription. Our study reveals for the first time that MOF promotes global transcription by acetylating CDK9, providing a new strategy for exploring the comprehensive mechanism of the MOF-CDK9 axis in cellular processes.
    Keywords:  CDK9; MG149; MOF; acetylation; transcription
    DOI:  https://doi.org/10.1111/febs.17264
  57. bioRxiv. 2024 Aug 28. pii: 2024.08.27.609996. [Epub ahead of print]
    Nuclear actin is a critical regulator of Drosophila female germline stem cell maintenance.
    Nicole M Green, Danielle Talbot, Tina L Tootle.
      Nuclear actin has been implicated in regulating cell fate, differentiation, and cellular reprogramming. However, its roles in development and tissue homeostasis remain largely unknown. Here we uncover the role of nuclear actin in regulating stemness using Drosophila ovarian germline stem cells (GSCs) as a model. We find that the localization and structure of nuclear actin is dynamic in the early germ cells. Nuclear actin recognized by anti-actin C4 is found in both the nucleoplasm and nucleolus of GSCs. The polymeric nucleoplasmic C4 pool is lost after the 2-cell stage, whereas the monomeric nucleolar pool persists to the 8-cell stage, suggesting that polymeric nuclear actin may contribute to stemness. To test this idea, we overexpressed nuclear targeted actin constructs to alter nuclear actin polymerization states in the GSCs and early germ cells. Increasing monomeric nuclear actin, but not polymerizable nuclear actin, causes GSC loss that ultimately results in germline loss. This GSC loss is rescued by simultaneous overexpression of monomeric and polymerizable nuclear actin. Together these data reveal that GSC maintenance requires polymeric nuclear actin. This polymeric nuclear actin likely plays numerous roles in the GSCs, as increasing monomeric nuclear actin disrupts nuclear architecture causing nucleolar hypertrophy, distortion of the nuclear lamina, and heterochromatin reorganization; all factors critical for GSC maintenance and function. These data provide the first evidence that nuclear actin, and in particular, its ability to polymerize, are critical for stem cell function and tissue homeostasis in vivo .
    DOI:  https://doi.org/10.1101/2024.08.27.609996
  58. Prog Mol Biol Transl Sci. 2024 ;pii: S1877-1173(24)00154-6. [Epub ahead of print]208 161-183
    Advances in CRISPR/Cas systems-based cell and gene therapy.
    Arpita Poddar, Farah Ahmady, Prashanth Prithviraj, Rodney B Luwor, Ravi Shukla, Shakil Ahmed Polash, Haiyan Li, Suresh Ramakrishna, George Kannourakis, Aparna Jayachandran.
      Cell and gene therapy are innovative biomedical strategies aimed at addressing diseases at their genetic origins. CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) systems have become a groundbreaking tool in cell and gene therapy, offering unprecedented precision and versatility in genome editing. This chapter explores the role of CRISPR in gene editing, tracing its historical development and discussing biomolecular formats such as plasmid, RNA, and protein-based approaches. Next, we discuss CRISPR delivery methods, including viral and non-viral vectors, followed by examining the various engineered CRISPR variants for their potential in gene therapy. Finally, we outline emerging clinical applications, highlighting the advancements in CRISPR for breakthrough medical treatments.
    Keywords:  CRISPR; Cas; Cell; Gene; Non-viral vector; Therapy; Viral vector
    DOI:  https://doi.org/10.1016/bs.pmbts.2024.07.005
  59. Int J Cancer. 2024 Sep 07.
    Enhanced pharmacological activities of AKR1C3-activated prodrug AST-3424 in cancer cells with defective DNA repair.
    Fanying Meng, Tianyang Qi, Xing Liu, Yizhi Wang, Jibing Yu, Zhaoqiang Lu, Xiaohong Cai, Anrong Li, Don Jung, Jianxin Duan.
      AST-3424 is a novel and highly tumor-selective prodrug. AST-3424 is activated by AKR1C3 to release a toxic bis-alkylating moiety, AST 2660. In this study, we have investigated the essential role of DNA repair in AST-3424 mediated pharmacological activities in vitro and in vivo. We show here that AST-3424 is effective as a single therapeutic agent against cancer cells to induce cytotoxicity, DNA damage, apoptosis and cell cycle arrest at G2 phase in a dose- and AKR1C3-dependent manner in both p53-proficient H460 (RRID:CVCL_0459) and p53-deficient HT-29 cells (RRID:CVCL_0320). The combination of abrogators of G2 checkpoint with AST-3424 was only synergistic in HT-29 but not in H460 cells. The enhanced activity of AST-3424 in HT-29 cells was due to impaired DNA repair ability via the attenuation of cell cycle G2 arrest and reduced RAD51 expression. Furthermore, we utilized a BRCA2 deficient cell line and two PDX models with BRCA deleterious mutations to study the increased activity of AST-3424. The results showed that AST-3424 exhibited enhanced in vitro cytotoxicity and superior and durable in vivo anti-tumor effects in cells deficient of DNA repair protein BRCA2. In summary, we report here that when DNA repair capacity is reduced, the in vitro and in vivo activity of AST-3424 can be further enhanced, thus providing supporting evidence for the further evaluation of AST-3424 in the clinic.
    Keywords:  AKR1C3; AST‐3424; DNA repair; cell cycles; p53
    DOI:  https://doi.org/10.1002/ijc.35170
  60. EMBO Mol Med. 2024 Sep 06.
    The influence of AHR on immune and tissue biology.
    Brigitta Stockinger, Oscar E Diaz, Emma Wincent.
      The aryl hydrocarbon receptor is a ligand dependent transcription factor which functions as an environmental sensor. Originally discovered as the sensor for man made pollutants such as 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) it has recently gained prominence as an important mediator for environmental triggers via the diet or microbiota which influences many physiological functions in different cell types and tissues across the body. Notably AHR activity contributes to prevent excessive inflammation following tissue damage in barrier organs such as skin, lung or gut which has received wide attention in the past decade. In this review we will focus on emerging common AHR functions across cell types and tissues and discuss ongoing issues that confound the understanding of AHR physiology. Furthermore, we will discuss the need for deeper molecular understanding of the functional activity of AHR in different contexts with respect to development of potential therapeutic applications.
    Keywords:  Aryl Hydrocarbon Receptor; Barrier Organs; Cytochrome P4501; Intestinal Epithelium; Tissue Repair
    DOI:  https://doi.org/10.1038/s44321-024-00135-w
  61. Nucleic Acids Res. 2024 Sep 13. pii: gkae786. [Epub ahead of print]
    Reconstruction of a robust bacterial replication module.
    Tao Wang, Fan He, Ting He, Chen Lin, Xin Guan, Zhongjun Qin, Xiaoli Xue.
      Chromosomal DNA replication is a fundamental process of life, involving the assembly of complex machinery and dynamic regulation. In this study, we reconstructed a bacterial replication module (pRC) by artificially clustering 23 genes involved in DNA replication and sequentially deleting these genes from their naturally scattered loci on the chromosome of Escherichia coli. The integration of pRC into the chromosome, moving from positions farther away to close to the replication origin, leads to an enhanced efficiency in DNA synthesis, varying from lower to higher. Strains containing replication modules exhibited increased DNA replication by accelerating the replication fork movement and initiating chromosomal replication earlier in the replication cycle. The minimized module pRC16, containing only replisome and elongation encoding genes, exhibited chromosomal DNA replication efficiency comparable to that of pRC. The replication module demonstrated robust and rapid DNA replication, regardless of growth conditions. Moreover, the replication module is plug-and-play, and integrating it into Mb-sized extrachromosomal plasmids improves their genetic stability. Our findings indicate that DNA replication, being a fundamental life process, can be artificially reconstructed into replication functional modules. This suggests potential applications in DNA replication and the construction of synthetic modular genomes.
    DOI:  https://doi.org/10.1093/nar/gkae786
  62. Ren Fail. 2024 Dec;46(2): 2398712
    Podocyte senescence: from molecular mechanisms to therapeutics.
    Qian Zhao, Yongzhang Huang, Ningying Fu, Caixia Cui, Xuan Peng, Haiyan Kang, Jie Xiao, Guibao Ke.
      As an important component of the glomerular filtration membrane, the state of the podocytes is closely related to kidney function, they are also key cells involved in aging and play a central role in the damage caused by renal aging. Therefore, understanding the aging process of podocytes will allow us to understand their susceptibility to injury and identify targeted protective mechanisms. In fact, the process of physiological aging itself can induce podocyte senescence. Pathological stresses, such as oxidative stress, mitochondrial damage, secretion of senescence-associated secretory phenotype, reduced autophagy, oncogene activation, altered transcription factors, DNA damage response, and other factors, play a crucial role in inducing premature senescence and accelerating aging. Senescence-associated-β-galactosidase (SA-β-gal) is a marker of aging, and β-hydroxybutyric acid treatment can reduce SA-β-gal activity to alleviate cellular senescence and damage. In addition, CCAAT/enhancer-binding protein-α, transforming growth factor-β signaling, glycogen synthase kinase-3β, cycle-dependent kinase, programmed cell death protein 1, and plasminogen activator inhibitor-1 are closely related to aging. The absence or elevation of these factors can affect aging through different mechanisms. Podocyte injury is not an independent process, and injured podocytes interact with the surrounding epithelial cells or other kidney cells to mediate the injury or loss of podocytes. In this review, we discuss the manifestations, molecular mechanisms, biomarkers, and therapeutic drugs for podocyte senescence. We included elamipretide, lithium, calorie restriction, rapamycin; and emerging treatment strategies, such as gene and immune therapies. More importantly, we summarize how podocyte interact with other kidney cells.
    Keywords:  Podocyte senescence; biomarkers; intervention targets; molecular mechanisms
    DOI:  https://doi.org/10.1080/0886022X.2024.2398712
  63. Cell Rep. 2024 Sep 11. pii: S2211-1247(24)01075-1. [Epub ahead of print]43(9): 114724
    Hyperactivating EZH2 to augment H3K27me3 levels in regulatory T cells enhances immune suppression by driving early effector differentiation.
    Janneke G C Peeters, Stephanie Silveria, Merve Ozdemir, Srinivas Ramachandran, Michel DuPage.
      The immunosuppressive function of regulatory T (Treg) cells is essential for maintaining immune homeostasis. Enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 (H3K27) methyltransferase, plays a key role in maintaining Treg cell function upon CD28 co-stimulation, and Ezh2 deletion in Treg cells causes autoimmunity. Here, we assess whether increasing H3K27me3 levels, by using an Ezh2Y641F gain-of-function mutation, will improve Treg cell function. We find that Treg cells expressing Ezh2Y641F display an effector Treg phenotype, are poised for improved homing to organ tissues, and can accelerate remission from autoimmunity. The H3K27me3 landscape and transcriptome of naive Ezh2Y641F Treg cells exhibit a redistribution of H3K27me3 modifications that recapitulates the gene expression profile of activated Ezh2WT Treg cells after CD28 co-stimulation. Altogether, increased H3K27me3 levels promote the differentiation of effector Treg cells that can better suppress autoimmunity.
    Keywords:  CP: Immunology; EZH2; autoimmunity; epigenetics; regulatory T cells
    DOI:  https://doi.org/10.1016/j.celrep.2024.114724
  64. bioRxiv. 2024 Aug 29. pii: 2024.08.28.610198. [Epub ahead of print]
    Cellular processing of beneficial de novo emerging proteins.
    Carly J Houghton, Nelson Castilho Coelho, Annette Chiang, Stefanie Hedayati, Saurin B Parikh, Nejla Ozbaki-Yagan, Aaron Wacholder, John Iannotta, Alexis Berger, Anne-Ruxandra Carvunis, Allyson F O'Donnell.
      Novel proteins can originate de novo from non-coding DNA and contribute to species-specific adaptations. It is challenging to conceive how de novo emerging proteins may integrate pre-existing cellular systems to bring about beneficial traits, given that their sequences are previously unseen by the cell. To address this apparent paradox, we investigated 26 de novo emerging proteins previously associated with growth benefits in yeast. Microscopy revealed that these beneficial emerging proteins preferentially localize to the endoplasmic reticulum (ER). Sequence and structure analyses uncovered a common protein organization among all ER-localizing beneficial emerging proteins, characterized by a short hydrophobic C-terminus immediately preceded by a transmembrane domain. Using genetic and biochemical approaches, we showed that ER localization of beneficial emerging proteins requires the GET and SND pathways, both of which are evolutionarily conserved and known to recognize transmembrane domains to promote post-translational ER insertion. The abundance of ER-localizing beneficial emerging proteins was regulated by conserved proteasome- and vacuole-dependent processes, through mechanisms that appear to be facilitated by the emerging proteins' C-termini. Consequently, we propose that evolutionarily conserved pathways can convergently govern the cellular processing of de novo emerging proteins with unique sequences, likely owing to common underlying protein organization patterns.
    DOI:  https://doi.org/10.1101/2024.08.28.610198
  65. Sci Transl Med. 2024 Sep 11. 16(764): eadg1777
    Targeted partial reprogramming of age-associated cell states improves markers of health in mouse models of aging.
    Sanjeeb Kumar Sahu, Pradeep Reddy, Jinlong Lu, Yanjiao Shao, Chao Wang, Mako Tsuji, Estrella Nuñez Delicado, Concepcion Rodriguez Esteban, Juan Carlos Izpisua Belmonte.
      Aging is a complex multifactorial process associated with epigenome dysregulation, increased cellular senescence, and decreased rejuvenation capacity. Short-term cyclic expression of octamer-binding transcription factor 4 (Oct4), sex-determining region Y-box 2 (Sox2), Kruppel-like factor 4 (Klf4), and cellular myelocytomatosis oncogene (cMyc) (OSKM) in wild-type mice improves health but fails to distinguish cell states, posing risks to healthy cells. Here, we delivered a single dose of adeno-associated viruses (AAVs) harboring OSK under the control of the cyclin-dependent kinase inhibitor 2a (Cdkn2a) promoter to specifically partially reprogram aged and stressed cells in a mouse model of Hutchinson-Gilford progeria syndrome (HGPS). Mice showed reduced expression of proinflammatory cytokines and extended life spans upon aged cell-specific OSK expression. The bone marrow and spleen, in particular, showed pronounced gene expression changes, and partial reprogramming in aged HGPS mice led to a shift in the cellular composition of the hematopoietic stem cell compartment toward that of young mice. Administration of AAVs carrying Cdkn2a-OSK to naturally aged wild-type mice also delayed aging phenotypes and extended life spans without altering the incidence of tumor development. Furthermore, intradermal injection of AAVs carrying Cdkn2a-OSK led to improved wound healing in aged wild-type mice. Expression of CDKN2A-OSK in aging or stressed human primary fibroblasts led to reduced expression of inflammation-related genes but did not alter the expression of cell cycle-related genes. This targeted partial reprogramming approach may therefore facilitate the development of strategies to improve health and life span and enhance resilience in the elderly.
    DOI:  https://doi.org/10.1126/scitranslmed.adg1777
  66. Biogerontology. 2024 Sep 11.
    The opposite aging effect to single cell transcriptome profile among cell subsets.
    Daigo Okada.
      Comparing transcriptome profiling between younger and older samples reveals genes related to aging and provides insight into the biological functions affected by aging. Recent research has identified sex, tissue, and cell type-specific age-related changes in gene expression. This study reports the overall picture of the opposite aging effect, in which aging increases gene expression in one cell subset and decreases it in another cell subset. Using the Tabula Muris Senis dataset, a large public single-cell RNA sequencing dataset from mice, we compared the effects of aging in different cell subsets. As a result, the opposite aging effect was observed widely in the genes, particularly enriched in genes related to ribosomal function and translation. The opposite aging effect was observed in the known aging-related genes. Furthermore, the opposite aging effect was observed in the transcriptome diversity quantified by the number of expressed genes and the Shannon entropy. This study highlights the importance of considering the cell subset when intervening with aging-related genes.
    Keywords:  Aging; Bioinformatics; Single-cell RNA-seq
    DOI:  https://doi.org/10.1007/s10522-024-10138-2
  67. Biochem Soc Trans. 2024 Sep 09. pii: BST20240177. [Epub ahead of print]
    Histone H3 mutations and their impact on genome stability maintenance.
    Lucas D Caeiro, Ramiro E Verdun, Lluis Morey.
      Histones are essential for maintaining chromatin structure and function. Histone mutations lead to changes in chromatin compaction, gene expression, and the recruitment of DNA repair proteins to the DNA lesion. These disruptions can impair critical DNA repair pathways, such as homologous recombination and non-homologous end joining, resulting in increased genomic instability, which promotes an environment favorable to tumor development and progression. Understanding these mechanisms underscores the potential of targeting DNA repair pathways in cancers harboring mutated histones, offering novel therapeutic strategies to exploit their inherent genomic instability for better treatment outcomes. Here, we examine how mutations in histone H3 disrupt normal chromatin function and DNA damage repair processes and how these mechanisms can be exploited for therapeutic interventions.
    Keywords:  genome integrity; methylation; oncohistones
    DOI:  https://doi.org/10.1042/BST20240177
  68. Science. 2024 Sep 13. 385(6714): 1148-1149
    Hunt for longevity drugs gets new life.
    Mitch Leslie.
      Decades-old project has new funding and a new set of compounds to test.
    DOI:  https://doi.org/10.1126/science.adt0783
  69. FEBS Lett. 2024 Sep 09.
    RNA Modifications Shape Hematopoietic Stem Cell Aging: Beyond the Code.
    Inge van der Werf, Jenna Sneifer, Catriona Jamieson.
      Hematopoietic system aging is characterized by both hematopoietic stem cell (HSC) and niche degeneration resulting in myeloid lineage-biased differentiation, reduced B cell and T cell lymphopoiesis, increased HSC mobilization, and fat deposition in the bone marrow. Both alterations in RNA splicing and editing during HSC aging contribute to increased myeloid lineage skewing and inflammation-responsive transcription factors, underscoring the importance of epitranscriptomic mechanisms in the acquisition of an age-related phenotype.
    Keywords:  ADAR1; APOBEC3; Aging; Hematopoiesis; RNA Editing; RNA Splicing; Stem Cells
    DOI:  https://doi.org/10.1002/1873-3468.15014
  70. Cancer Res. 2024 Sep 12.
    Targeting Fatty Acid Metabolism Abrogates the Differentiation Blockade in Pre-leukemic Cells.
    Xiaoyu Liu, Yu Liu, Qing Rao, Yihan Mei, Haiyan Xing, Runxia Gu, Junli Mou, Manling Chen, Fan Ding, Wanqing Xie, Kejing Tang, Zheng Tian, Min Wang, Shaowei Qiu, Jianxiang Wang.
      Metabolism plays a key role in the maintenance of normal hematopoietic stem cells (HSCs) and in the development of leukemia. A better understanding of the metabolic characteristics and dependencies of pre-leukemic cells could help identify potential therapeutic targets to prevent leukemic transformation. As AML1-ETO, one of the most frequent fusion proteins in acute myeloid leukemia that is encoded by a RUNX1::RUNX1T1 fusion gene, is capable of generating pre-leukemic clones, here we used a conditional Runx1::Runx1t1 knock-in mouse model to evaluate pre-leukemic cell metabolism. AML1-ETO expression resulted in impaired hematopoietic reconstitution and increased self-renewal ability. Oxidative phosphorylation and glycolysis decreased significantly in these pre-leukemic cells accompanied by increased HSC quiescence and reduced cell cycling. Furthermore, HSCs expressing AML1-ETO exhibited an increased requirement for fatty acids through metabolic flux. Dietary lipid deprivation or loss of the fatty acid transporter FATP3 by targeted deletion using CRISPR/Cas9 partially restored differentiation. These findings reveal the unique metabolic profile of pre-leukemic cells and propose FATP3 as a potential target for disrupting leukemogenesis.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-3861
  71. Exp Cell Res. 2024 Sep 10. pii: S0014-4827(24)00342-2. [Epub ahead of print] 114251
    Impaired Incorporation of Fibronectin into the Extracellular Matrix during Aging Exacerbates the Senescent State of Dermal Cells.
    Luce Perié, Cynthia Houël, Anne Zambon, Christelle Guere, Katell Vié, Johanne Leroy-Dudal, Charlotte Vendrely, Rémy Agniel, Franck Carreiras, Cédric R Picot.
      Fibronectin (Fn) is a ubiquitous extracellular matrix (ECM) glycoprotein that acts as an ECM scaffold organizer and is essential in many biological functions, including tissue repair ,differenciation or cancer dissemination. Evidence suggest that amount of Fn change during aging. However, how these changes influence the aging process remains unclear. This study aims to understand Fn influence on cell aging. First, we assess relative level of Fn abundance in both different biopsies skin donors and replicative senescence cellular model. In skin biopsies, we observed that Fn level decreases with aging in the reticular dermis, while its expression remains relatively stable in the papillary dermis, likely to sustain the dermis-epidermis junction. During replicative senescence, in BJ skin fibroblasts, while intracellular Fn increases, we found that secretion and Fn fibrils formation are less effective. Reduced Fn fibrils leads to disorganization of the ECM. This could be explained by the expression of different Fn isoforms observed in the secretome of senescent cells. Surprisingly, the knockdown of Fn delays the onset of senescence while cultivating cells onto a Fn-coated support promotes it. Taken together, these new insights on the role of Fn during aging may emerge new therapeutic strategies on aged-related diseases.
    Keywords:  Aging; Fibronectin; extracellular matrix remodeling; senescence; skin
    DOI:  https://doi.org/10.1016/j.yexcr.2024.114251
  72. Mucosal Immunol. 2024 Sep 06. pii: S1933-0219(24)00094-1. [Epub ahead of print]
    MicroRNA-142 regulates gut associated lymphoid tissues and group 3 innate lymphoid cells.
    Luke B Roberts, Joana F Neves, Dave C H Lee, Sara Valpione, Roser Tachó-Piñot, Jane K Howard, Matthew R Hepworth, Graham M Lord.
      The transcriptomic signatures that shape responses of innate lymphoid cells (ILCs) have been well characterised, however post-transcriptional mechanisms which regulate their development and activity remain poorly understood. We demonstrate that ILC groups of the intestinal lamina propria express mature forms of microRNA-142 (miR-142), an evolutionarily conserved microRNA family with several non-redundant regulatory roles within the immune system. Germline Mir142 deletion alters intestinal ILC compositions, resulting in the absence of T-bet+ populations and significant defects in the cellularity and phenotypes of ILC3 subsets including CCR6+ LTi-like ILC3s. These effects were associated with decreased pathology in an innate-immune cell driven model of colitis. Furthermore, Mir142-/- mice demonstrate defective development of gut-associated lymphoid tissues, including a complete absence of mature Peyer's patches. Conditional deletion of Mir142 in ILC3s (RorcΔMir142) supported cell-intrinsic roles for these microRNAs in establishing or maintaining cellularity and functions of LTi-like ILC3s in intestinal associated tissues. RNAseq analysis revealed several target genes and biological pathways potentially regulated by miR-142 microRNAs in these cells. Finally, lack of Mir142 in ILC3 led to elevated IL-17A production. These data broaden our understanding of immune system roles of miR-142 microRNAs, identifying these molecules as critical post-transcriptional regulators of ILC3s and intestinal mucosal immunity.
    Keywords:  ILC3; Innate Lymphoid Cells; Intestine; Peyer’s Patches; miR-142
    DOI:  https://doi.org/10.1016/j.mucimm.2024.09.001
  73. Glob Med Genet. 2024 Dec;11(4): 304-311
    Role of Noncoding RNAs in Modulating Microglial Phenotype.
    Eiman Meer.
      Microglia are immunocompetent cells that are present in the retina and central nervous system, and are involved in the development maintenance and immune functions in these systems. Developing from yolk sac-primitive macrophages, they proliferate in the local tissues during the embryonic period without resorting to the production from the hematopoietic stem cells, and are critical in sustaining homeostasis and performing in disease and injury; they have morphological characteristics and distinct phenotypes according to the microenvironment. Microglia are also present in close association with resident cells in the retina where they engage in synapse formation, support normal functions, as well as immune defense. They are involved in the development of numerous neurodegenerative and ophthalmic diseases and act as diversity shields and triggers. Noncoding ribonucleic acids (ncRNAs) refer to RNA molecules synthesized from the mammalian genome, and these do not have protein-coding capacity. These ncRNAs play a role in the regulation of gene expression patterns. ncRNAs have only been recently identified as vastly significant molecules that are involved in the posttranscriptional regulation. Microglia are crucial for brain health and functions and current studies have focused on the effects caused by ncRNA on microglial types. Thus, the aim of the review was to provide an overview of the current knowledge about the regulation of microglial phenotypes by ncRNAs.
    Keywords:  inflammation; long noncoding RNAs; microRNA; microglia; noncoding RNAs
    DOI:  https://doi.org/10.1055/s-0044-1790283
  74. iScience. 2024 Sep 20. 27(9): 110644
    Disruption of perinatal myeloid niches impacts the aging clock of pancreatic β cells.
    Jessica O'Sell, Vincenzo Cirulli, Stephanie Pardike, Marie Aare-Bentsen, Patima Sdek, Jasmine Anderson, Dale W Hailey, Mary C Regier, Sina A Gharib, Laura Crisa.
      Perinatal expansion of pancreatic β cells is critical to metabolic adaptation. Yet, mechanisms surveying the fidelity by which proliferative events generate functional β cell pools remain unknown. We have previously identified a CCR2+ myeloid niche required for peri-natal β cell replication, with β cells dynamically responding to loss and repopulation of these myeloid cells with growth arrest and rebound expansion, respectively. Here, using a timed single-cell RNA-sequencing approach, we show that transient disruption of perinatal CCR2+ macrophages change islet β cell repertoires in young mice to resemble those of aged mice. Gene expression profiling and functional assays disclose prominent mitochondrial defects in β cells coupled to impaired redox states, NAD depletion, and DNA damage, leading to accelerated islets' dysfunction with age. These findings reveal an unexpected vulnerability of mitochondrial β cells' bioenergetics to the disruption of perinatal CCR2+ macrophages, implicating these cells in surveying early in life both the size and energy homeostasis of β cells populations.
    Keywords:  Cell biology; Immunology; Physiology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2024.110644
  75. Biochim Biophys Acta Mol Cell Res. 2024 Sep 10. pii: S0167-4889(24)00188-5. [Epub ahead of print] 119845
    SRSF2 is essential for maintaining pancreatic beta-cell identity and regulating glucose homeostasis in mice.
    Xue You, Qian Peng, Wenju Qian, Duan Huimin, Zhiqin Xie, Ying Feng.
      Diabetes is characterized by decreased beta-cell mass and islet dysfunction. The splicing factor SRSF2 plays a crucial role in cell survival, yet its impact on pancreatic beta cell survival and glucose homeostasis remains unclear. We observed that the deletion of Srsf2 specifically in beta cells led to time-dependent deterioration in glucose tolerance, impaired insulin secretion, decreased islet mass, an increased number of alpha cells, and the onset of diabetes by the age of 10 months in mice. Single-cell RNA sequencing (scRNA-seq) analyses revealed that, despite an increase in populations of unfolded protein response (UPR)-activated and undifferentiated beta cells within the SRSF2_KO group, there was a notable decrease in the expression of UPR-related and endoplasmic reticulum (ER)-related genes, accompanied by a loss of beta-cell identity. This suggests that beta cells have transitioned from an adaptive phase to a maladaptive phase in islets of 10-month-old SRSF2_KO mice. Further results demonstrated that deletion of SRSF2 caused decreased proliferation in beta cells within 3-month-old islets and Min6 cells. These findings underscore the essential role of SRSF2 in controlling beta-cell proliferation and preserving beta-cell function in mice.
    Keywords:  Beta-cell-specific knockout mice; SRSF2; decreased islet mass; scRNA-seq analyses
    DOI:  https://doi.org/10.1016/j.bbamcr.2024.119845
  76. PLoS Pathog. 2024 Sep 10. 20(9): e1012535
    Methylation of KSHV vCyclin by PRMT5 contributes to cell cycle progression and cell proliferation.
    Danping Niu, Yuanming Ma, Pengyu Ren, Sijia Chang, Chenhui Li, Yong Jiang, Chunyan Han, Ke Lan.
      Kaposi's sarcoma-associated herpesvirus (KSHV) is a double-stranded DNA virus that encodes numerous cellular homologs, including cyclin D, G protein-coupled protein, interleukin-6, and macrophage inflammatory proteins 1 and 2. KSHV vCyclin encoded by ORF72, is the homolog of cellular cyclinD2. KSHV vCyclin can regulate virus replication and cell proliferation by constitutively activating cellular cyclin-dependent kinase 6 (CDK6). However, the regulatory mechanism of KSHV vCyclin has not been fully elucidated. In the present study, we identified a host protein named protein arginine methyltransferase 5 (PRMT5) that interacts with KSHV vCyclin. We further demonstrated that PRMT5 is upregulated by latency-associated nuclear antigen (LANA) through transcriptional activation. Remarkably, knockdown or pharmaceutical inhibition (using EPZ015666) of PRMT5 inhibited the cell cycle progression and cell proliferation of KSHV latently infected tumor cells. Mechanistically, PRMT5 methylates vCyclin symmetrically at arginine 128 and stabilizes vCyclin in a methyltransferase activity-dependent manner. We also show that the methylation of vCyclin by PRMT5 positively regulates the phosphorylate retinoblastoma protein (pRB) pathway. Taken together, our findings reveal an important regulatory effect of PRMT5 on vCyclin that facilitates cell cycle progression and proliferation, which provides a potential therapeutic target for KSHV-associated malignancies.
    DOI:  https://doi.org/10.1371/journal.ppat.1012535
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