bims-caglex Biomed News
on Cellular aging and life extension
Issue of 2024–09–29
75 papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño
  1. The role of p21 in cellular senescence and aging-related diseases.
  2. The putative contribution of cellular senescence to driving tauopathies.
  3. The potential of flavonoids to mitigate cellular senescence in cardiovascular disease.
  4. Geraniol intake improves age-related malnutrition in mice.
  5. Temperature-dependent lifespan extension is achieved in miR-80-deleted Caenorhabditis elegans by NLP-45 to modulate endoplasmic reticulum unfolded protein responses.
  6. Stochasticity in Dietary Restriction-Mediated Lifespan Outcomes in Drosophila.
  7. Ellagitannin Component Punicalin Ameliorates Cognitive Dysfunction, Oxidative Stress, and Neuroinflammation via the Inhibition of cGAS-STING Signaling in the Brain of an Aging Mouse Model.
  8. M2 macrophage-derived exosomes promote tendon-to-bone healing by alleviating cellular senescence in aged rats.
  9. A Comprehensive Review of Stem Cell Conditioned Media Role for Anti-Aging on Skin.
  10. Glutathione peroxidase 3 is essential for countering senescence in adipose remodelling by maintaining mitochondrial homeostasis.
  11. NAD+ homeostasis and its role in exercise adaptation: A comprehensive review.
  12. Genome Editing Therapy for the Blood: Ex Vivo Success and In Vivo Prospects.
  13. E5 treatment showing improved health-span and lifespan in old Sprague Dawley rats.
  14. Anti-aging based on stem cell therapy: A scoping review.
  15. Senescence in the ageing skin: a new focus on mTORC1 and the lysosome.
  16. Programmable editing of primary MicroRNA switches stem cell differentiation and improves tissue regeneration.
  17. Exercise and nutrition benefit skeletal muscle: From influence factor and intervention strategy to molecular mechanism.
  18. A Novel Metabolomic Aging Clock Predicting Health Outcomes and Its Genetic and Modifiable Factors.
  19. Research advances in the function and anti-aging effects of nicotinamide mononucleotide.
  20. Tubular Aggregates as a Marker of Aging in Skeletal Muscle.
  21. Lycopene alleviates age-related cognitive deficit via activating liver-brain fibroblast growth factor-21 signalling.
  22. Protection of the genome and the central exome by peripheral non-coding DNA against DNA damage in health, ageing and age-related diseases.
  23. ALKBH5 Regulates Osteogenic Differentiation via the lncRNA/mRNA Complex.
  24. Tauroursodeoxycholic acid targets HSP90 to promote protein homeostasis and extends healthy lifespan.
  25. The Glutathione Theory of Aging.
  26. The impact of short-lived controls on the interpretation of lifespan experiments and progress in geroscience - through the lens of the "900-day rule".
  27. Estrogen, via ESR2 receptor, prevents oxidative stress-induced Müller cell death and stimulates FGF2 production independently of NRF2, attenuating retinal degeneration.
  28. Inflammatory Memory in Epidermal Stem Cells - A New Strategy for Recurrent Inflammatory Skin Diseases.
  29. A biocompatible polydopamine platform for targeted delivery of nicotinamide mononucleotide and boosting NAD+ levels in the brain.
  30. Senescence- and Immunity-Related Changes in the Central Nervous System: A Comprehensive Review.
  31. NuRD chromatin remodeling is required to repair exogenous DSBs in the Caenorhabditis elegans germline.
  32. Multifaceted roles of H2B mono-ubiquitylation in D-loop metabolism during homologous recombination repair.
  33. Delta Opioid Peptide [d-Ala2, d-Leu5]-Enkephalin Improves Physical and Cognitive Function and Increases Lifespan in Aged Female Mice.
  34. Getting to Know the Effect Theory of Traditional Pediatric Tuina in the View of Modern Medicine in Three Minor Perspectives.
  35. miR-96-5p expression is sufficient to induce and maintain the senescent cell fate in the absence of stress.
  36. Urolithin A prevents age-related hearing loss in C57BL/6J mice likely by inducing mitophagy.
  37. Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling in heavy metals-induced oxidative stress.
  38. Mitochondrial protein heterogeneity stems from the stochastic nature of co-translational protein targeting in cell senescence.
  39. The Multifaceted Protective Role of Nuclear Factor Erythroid 2-Related Factor 2 in Osteoarthritis: Regulation of Oxidative Stress and Inflammation.
  40. Benzimidazole-based small molecules as anticancer agents targeting telomeric G-quadruplex and inhibiting telomerase enzyme.
  41. Proteomic analysis across aged tissues reveals distinct signatures and the crucial involvement of midgut barrier function in the regulation of aging.
  42. Stem cells reverse woman's diabetes - a world first.
  43. Plant extracts and omega-3 improve short-term memory and modulate the microbiota-gut-brain axis in D-Galactose model mice.
  44. Targeting SERCA2 in Anti-Tumor Drug Discovery.
  45. Telomeres and immunodeficiencies.
  46. Identification of key genes and signaling pathways based on transcriptomic studies of aerobic and resistance training interventions in sarcopenia in SAMP8 mice.
  47. Skin wound repairing effects of adipose mesenchymal stem cells is promoted by the combined application of insulin-like growth factor 1: The key role of miR-21-5p-mediated signaling transduction.
  48. A longevity-specific bank of induced pluripotent stem cells from centenarians and their offspring.
  49. Rational design of bioengineered recombinant collagen-like protein enhances GelMA hydrogel for diabetic wound healing.
  50. ZNF521 promotes acute myeloid leukemogenesis by suppressing the expression and acetylation of SMC3.
  51. Advances in Zinc-Containing Bioactive Glasses: A Comprehensive Review.
  52. Traffic light at DSB-transit regulation between gene transcription and DNA repair.
  53. Deciphering the spatial distribution of Gli1-lineage cells in dental, oral, and craniofacial regions.
  54. Comparison of Bioengineered Scaffolds for the Induction of Osteochondrogenic Differentiation of Human Adipose-Derived Stem Cells.
  55. Exercise-Induced Shear Stress Drives mRNA Translation In Vitro.
  56. Extra-osseous Roles of the RANK-RANKL-OPG Axis with a Focus on Skeletal Muscle.
  57. New insights into the role of Klotho in inflammation and fibrosis: molecular and cellular mechanisms.
  58. Hydrogen sulfide mitigates mitochondrial dysfunction and cellular senescence in diabetic patients: Potential therapeutic applications.
  59. Role of the SAF-A SAP domain in X inactivation, transcription, splicing, and cell proliferation.
  60. Dihydroavenanthramide D Enhances Skin Barrier Function through Upregulation of Epidermal Tight Junction Expression.
  61. Correction to: The Hox-based positional memory in muscle stem cells.
  62. Phase separation of hnRNPA1 and TERRA regulates telomeric stability.
  63. Metabolic regulation in normal and leukemic stem cells.
  64. Neurodegeneration: Effects of Calorie Restriction on the Brain Sirtuin Protein Levels.
  65. Exploring tryptophan metabolism: The transition from disturbed balance to diagnostic and therapeutic potential in metabolic diseases.
  66. miR-27a-3p regulates intestinal cell proliferation and differentiation through Wnt/β-catenin signalling.
  67. Early Life Interventions: Impact on Aging and Longevity.
  68. Asynchronous changes of hydrogen sulfide and its generating enzymes in most tissues with the aging process.
  69. OligoFormer: An accurate and robust prediction method for siRNA design.
  70. Effect of senolytic drugs in young female mice chemically induced to estropause.
  71. Investigation of Nrf2-Keap-1 pathway, Sestrin 2 and oxidative stress markers in serum of patients with placenta Accreata spectrum.
  72. CPEB2-activated Prdm16 translation promotes brown adipocyte function and prevents obesity.
  73. Clearance of senescent cells enhances skin wound healing in type 2 diabetic mice.
  74. Ionic release from bioactive SiO2-CaOCME/poly(tetrahydrofuran)/poly(caprolactone) hybrids drives human-bone marrow stromal cell osteogenic differentiation.
  75. Enhanced CRISPR/Cas-Based Immunoassay through Magnetic Proximity Extension and Detection.
  1. Mol Cells. 2024 Sep 18. pii: S1016-8478(24)00138-9. [Epub ahead of print] 100113
    The role of p21 in cellular senescence and aging-related diseases.
    Jiayu Yan, Siyi Chen, Zimei Yi, Ruowen Zhao, Jiayu Zhu, Shuwen Ding, Junhua Wu.
      During the aging process or disease progression, normal cells and tissues in the body undergo various stresses, leading to cell damage and the need for repair, adaptation, apoptosis, or defense responses. Cellular senescence is a key player in this process, influencing the rate of aging and disease progression. It can be triggered by different stress factors, resulting in irreversible cell cycle arrest and functional decline. Senescent cells often show high expression of cell cycle factors like p21 and p16, which are involved in cell cycle arrest. p16 has long been recognized as a significant marker of aging. Recent evidence suggests that p21high cells and p16high cells represent distinct cell populations in terms of cell type, tissue location, accumulation kinetics, and physiological functions. This article focuses on recent advancements in understanding p21-dependent cellular senescence. It starts by providing an overview of the role of p21 in three primary cellular senescence phenotypes where it plays a crucial role. It then delves into the pathogenesis of diseases closely linked to p21-dependent cellular senescence, particularly metabolic disorders and cardiovascular diseases. The article also discusses progress in p21-related animal models and outlines strategies for utilizing p21 to intervene in cellular senescence by delaying aging, eliminating senescent cells, and rejuvenating senescent cells. This review systematically examines the pathogenesis of p21-dependent cellular senescence, emphasizing its importance in studying aging heterogeneity and developing new senolytic therapies. It aims to stimulate future research on leveraging p21 to enhance the characteristics of senescent cells, allowing more precise methods for eliminating harmful senescent cells at the right time, thereby delaying aging and potentially achieving rejuvenation.
    Keywords:  aging-related diseases; cellular senescence; p21; senolytic; senomorphic
    DOI:  https://doi.org/10.1016/j.mocell.2024.100113
  2. Trends Immunol. 2024 Sep 20. pii: S1471-4906(24)00192-3. [Epub ahead of print]
    The putative contribution of cellular senescence to driving tauopathies.
    Deniz Karabag, Michael T Heneka, Christina Ising.
      During mammalian aging, senescent cells accumulate in the body. Recent evidence suggests that senescent cells potentially contribute to age-related neurodegenerative diseases in the central nervous system (CNS), including tauopathies such as Alzheimer's disease (AD). Senescent cells undergo irreversible cell cycle arrest and release an inflammatory 'senescence-associated secretory profile' (SASP), which can exert devastating effects on surrounding cells. Senescent markers and SASP factors have been detected in multiple brain cells in tauopathies, including microglia, astrocytes, and perhaps even post-mitotic neurons, possibly contributing to the initiation as well as progression of these diseases. Here, we discuss the implications of presenting a senescent phenotype in tauopathies and highlight a potential role for the NOD-like receptor protein 3 (NLRP3) inflammasome as a newfound mechanism implicated in senescence and SASP formation.
    Keywords:  Alzheimer’s disease; aging; cellular senescence; senescence-associated secretory phenotype; tauopathies
    DOI:  https://doi.org/10.1016/j.it.2024.08.006
  3. Biogerontology. 2024 Sep 26.
    The potential of flavonoids to mitigate cellular senescence in cardiovascular disease.
    Huimin Zheng, Tiantian Li, Ziyun Hu, Qi Zheng, Junsong Wang.
      Aging is one of the most significant factors affecting cardiovascular health, with cellular senescence being a central hallmark. Senescent cells (SCs) secrete a specific set of signaling molecules known as the senescence-associated secretory phenotype (SASP). The SASP has a remarkable impact on age-associated diseases, particularly cardiovascular diseases (CVD). Targeting SCs through anti-aging therapies represents a novel strategy to effectively retard senescence and attenuate disease progression. Accumulating evidence demonstrates that the flavonoids, widely presented in fruits and vegetables worldwide, can delay or treat CVD via selectively eliminating SCs (senolytics) and modulating SASPs (senomorphics). Nevertheless, only sporadic research has illustrated the application of flavonoids in targeting SCs for CVD, which requires further exploration. This review recapitulates the hallmarks and key molecular mechanisms involved in cellular senescence, then summarizes senescence of different types of cardiac cells and describes the mechanisms by which cellular senescence affects CVD development. The discussion culminates with the potential use of flavonoids via exerting their biological effects on cellular senescence to reduce CVD incidence. This summary will provide valuable insights for cardiovascular drug design, development and clinical applications leveraging flavonoids.
    Keywords:  Cardiovascular diseases; Cellular senescence; Flavonoids; Hormesis; Senolytics; Senomorphics
    DOI:  https://doi.org/10.1007/s10522-024-10141-7
  4. Geriatr Gerontol Int. 2024 Sep 24.
    Geraniol intake improves age-related malnutrition in mice.
    Shuichi Shibuya, Kenji Watanabe, Daiki Sakuraba, Takeshi Nagata, Yoshimasa Yamaguchi, Yasuyuki Suzuki, Takahiko Shimizu.
       AIM: Geraniol is an acyclic monoterpenoid that is abundant in many plants, including rose, lemongrass, and lavender. As geraniol has various beneficial functions, rose oil rich in geraniol is not only used for aromatherapy but also as a supplement to promote health benefits. However, the beneficial effects of geraniol on age-related pathologies are unknown. In this study, we aimed to clarify the effects of geraniol intake on age-related pathologies.
    METHODS: We orally administered geraniol to aged mice (age: 24-29 months) five times a week for 4 weeks and sampled their blood and various organs. We investigated age-related changes in the blood and organ samples. Furthermore, we treated HepG2 cells with geraniol and examined the expression level of the ALB gene and the amount of secreted albumin in vitro.
    RESULTS: Geraniol significantly increased blood albumin, total cholesterol, and red blood cell counts, indicating an improvement in nutritional markers in aged mice. Geraniol also transcriptionally increased the Alb gene expression in the liver of aged mice. Furthermore, treatment with geraniol significantly upregulated the ALB gene expression and the secretion of albumin in the conditioned medium of HepG2 cells.
    CONCLUSION: Geraniol increases serum albumin levels at the transcriptional level. Geraniol intake can be an effective strategy for age-related malnutrition. Geriatr Gerontol Int 2024; ••: ••-••.
    Keywords:  aging; albumin; food; geraniol; malnutrition
    DOI:  https://doi.org/10.1111/ggi.14982
  5. Aging Cell. 2024 Sep 25. e14345
    Temperature-dependent lifespan extension is achieved in miR-80-deleted Caenorhabditis elegans by NLP-45 to modulate endoplasmic reticulum unfolded protein responses.
    Chunlin Zhao, Jintao Luo, Yuqiang Zhang, Yong Yu.
      MicroRNA plays a crucial role in post-transcriptional gene regulation and has recently emerged as a factor linked to aging, but the underlying regulatory mechanisms remain incompletely understood. In this study, we observed lifespan-extending effects in miR-80-deficient Caenorhabditis elegans at 20°C but not 25°C. At 20°C, miR-80 deletion leads to NLP-45 upregulation, which positively correlates to increased abu transcripts and extended lifespan. Supportively, we identified miR-80 binding regions in the 5' and 3' UTR of nlp-45. As the temperature rises to 25°C, wildtype increases miR-80 levels, but removal of miR-80 is accompanied by decreased nlp-45 expression, suggesting intervention from other temperature-sensitive mechanisms. These findings support the concept that microRNAs and neuropeptide-like proteins can form molecular regulatory networks involving downstream molecules to regulate lifespan, and such regulatory effects vary on environmental conditions. This study unveils the role of an axis of miR-80/NLP-45/UPRER components in regulating longevity, offering new insights on strategies of aging attenuation and health span prolongation.
    Keywords:   Caenorhabditis elegans ; miR‐80 ; NLP‐45; aging; endoplasmic reticulum stress
    DOI:  https://doi.org/10.1111/acel.14345
  6. bioRxiv. 2024 Sep 12. pii: 2024.09.06.611756. [Epub ahead of print]
    Stochasticity in Dietary Restriction-Mediated Lifespan Outcomes in Drosophila.
    Olivia L Mosley, Joel A Villa, Advaitha Kamalakkannan, Eliyashaib James, Jessica M Hoffman, Yang Lyu.
      Dietary restriction (DR) is widely considered to be one of the most potent approaches to extend healthy lifespan across various species, yet it has become increasingly apparent that DR-mediated longevity is influenced by biological and non-biological factors. We propose that current priorities in the field should include understanding the relative contributions of these factors to elucidate the mechanisms underlying the beneficial effects of DR. Our work conducted in two laboratories, represents an attempt to unify DR protocols in Drosophila and to investigate the stochastic effects of DR. Across 64 pairs of survival data (DR/ad libitum, or AL), we find that DR does not universally extend lifespan. Specifically, we observed that DR conferred a significant lifespan extension in only 26.7% (17/64) of pairs. Our pooled data show that the overall lifespan difference between DR and AL groups is statistically significant, but the median lifespan increase under DR (7.1%) is small. The effects of DR were overshadowed by stochastic factors and genotype. Future research efforts directed toward gaining a comprehensive understanding of DR-dependent mechanisms should focus on unraveling the interactions between genetic and environmental factors. This is essential for developing personalized healthspan-extending interventions and optimizing dietary recommendations for individual genetic profiles.
    DOI:  https://doi.org/10.1101/2024.09.06.611756
  7. Phytother Res. 2024 Sep 23.
    Ellagitannin Component Punicalin Ameliorates Cognitive Dysfunction, Oxidative Stress, and Neuroinflammation via the Inhibition of cGAS-STING Signaling in the Brain of an Aging Mouse Model.
    Peng Chen, Zhongyuan Zhang, Jiexin Lei, Jun Zhu, Gang Liu.
      Despite remarkable breakthroughs in pharmacotherapy, many potential therapies for aging remain unexplored. Punicalin (PUN), an ellagitannin component, exerts anti-inflammatory, antioxidant, and anti-apoptotic effects. This study investigated the beneficial effects of PUN against age-related brain damage in mice and explored the underlying mechanisms. We validated the protective effects of PUN against D-galactose (D-gal)-induced neuroinflammation and subsequent neuronal damage in BV2 microglia and N2a cells, respectively, in vitro. In vivo experiments were conducted on mice that were administered an 8-week regimen of intraperitoneal injections of D-gal at a dosage of 150 mg/kg/day, concurrently with oral gavage of PUN at the same dose. PUN inhibited the production of D-gal-induced inflammatory cytokines (iNOS, COX2, TNF-α, IL-6, IL-2, and IL-1β) in BV2 cells and conferred protection to N2a cells against synaptic damage mediated by BV2 microglia-induced neuroinflammation. The in vivo findings revealed that PUN considerably improved memory and learning deficits, reduced MDA levels, enhanced GSH-Px, CAT, and SOD activities, and modulated the expression of inflammatory proteins such as iNOS, COX-2, IL-1β, IL-2, IL-6, and TNF-α. Furthermore, PUN inhibited the secretion of SASP factors (ICAM-1, PAI-1, MMP-3, and MMP-9), decreased microglial activation, and reduced astrocytosis. Additionally, PUN suppressed the expression of cGAS, p-STING, p-TBK1, p-p65, and p-IRF3 in aging mouse brains and cultured BV2 microglia. In conclusion, PUN improved cognitive dysfunction in aging mice through antioxidant and anti-inflammatory mechanisms via inhibition of the cGAS-STING pathway, suggesting that it can be a promising therapeutic agent for brain aging and aging-related diseases.
    Keywords:  aging; cGAS‐STING; cognitive defects; neuroinflammation; punicalin
    DOI:  https://doi.org/10.1002/ptr.8343
  8. Arthroscopy. 2024 Sep 24. pii: S0749-8063(24)00737-0. [Epub ahead of print]
    M2 macrophage-derived exosomes promote tendon-to-bone healing by alleviating cellular senescence in aged rats.
    Zhuochang Cai, Longqiang Shu, Chongyang Wang, Xuetao Xie, Xudong Liu.
       PURPOSE: To explore the potential of M2 macrophage-derived exosomes (M2-Exos) in enhancing tendon-to-bone healing in aged rats by mitigating cellular senescence of bone marrow-derived stem cells (BMSCs).
    METHODS: In vitro, effects of M2-Exos on alleviating cellular senescence and improving chondrogenic potential of senescent BMSCs were evaluated. Twenty-four young and forty-eight aged rats with chronic rotator cuff tear (RCT) were repaired and assigned into three groups: young group (young rats injected with fibrin at the enthesis), aged group (aged rats injected with fibrin at the enthesis), and aged + M2-Exos group (aged rats injected with fibrin containing M2-Exos at the enthesis). Six and twelve weeks after repair, enthesis regeneration was evaluated. Proteomic analysis was conducted to explore the mechanism through which M2-Exos mitigated cellular senescence.
    RESULTS: In senescent BMSCs treated with M2-Exos, there was a reduction in senescence biomarkers including senescence-associated β-galactosidase, p53, p21 and senescence associated secretory phenotype (P < .001). M2-Exos also enhanced chondrogenic potential of senescent BMSCs, reflected in higher Bern score (P < .001) and increased expression of Sox9 (P = .013), Col2a1 (P < .001), and Acan (P < .001). Histologically, aged rats treated with M2-Exos demonstrated significantly higher histological scores (P < .001 at both 6 and 12 weeks) and increased fibrocartilage regeneration at the enthesis. Biomechanically, these rats exhibited greater failure load, stiffness, and stress (all P < .001) at 12 weeks. Mechanistically, proteomic analysis suggested that M2-Exos might alleviate cellular senescence by potentially regulating DNA replication and repair.
    CONCLUSION: M2-Exos can significantly alleviate BMSC senescence and thereby enhance tendon-to-bone healing in an aged rat RCT model.
    CLINICAL RELEVANCE: This study suggests the potential utility of M2-Exos as a therapy for RCT in the older population.
    DOI:  https://doi.org/10.1016/j.arthro.2024.09.021
  9. Stem Cells Cloning. 2024 ;17 5-19
    A Comprehensive Review of Stem Cell Conditioned Media Role for Anti-Aging on Skin.
    Ayatulloh Alquraisy, Gofarana Wilar, Ahmed Fouad Abdelwahab Mohammed, Ali El-Rayyes, Cecep Suhandi, Nasrul Wathoni.
      Various studies have been widely conducted on conditioned medium for the development of anti-aging preparations, including the utilization of stem cells, which present a promising alternative solution. This narrative review aims to understand the latest developments in various conditioned medium stem cell applications for anti-aging on the skin. A search of the Scopus database yielded publications of interest. The research focused on articles published without restrictions on the year. After finding 68 articles in the search results, they moved on to the checking phase. Upon comprehensive literature review, 23 articles met the inclusion criteria, while 45 articles were deemed ineligible for participation in this research. The results of the review indicate that conditioned medium from various stem cells has demonstrated success in reducing risk factors for skin aging, as proven in various tests. The successful reduction of the risk of skin aging has been established in vitro, in vivo, and in clinical trials. Given the numerous studies on the progress of exploring and utilizing conditioned medium, it is expected to provide a solution to the problem of skin aging.
    Keywords:  anti-aging; conditioned medium; skin aging; stem cell
    DOI:  https://doi.org/10.2147/SCCAA.S480437
  10. Redox Biol. 2024 Sep 19. pii: S2213-2317(24)00343-4. [Epub ahead of print]77 103365
    Glutathione peroxidase 3 is essential for countering senescence in adipose remodelling by maintaining mitochondrial homeostasis.
    Yijie Song, Mengjie Zhu, Md Ariful Islam, Wenyi Gu, Kavsar Alim, Chien-Shan Cheng, Jingxian Chen, Yu Xu, Hongxi Xu.
      Adipose tissue senescence is a precursor to organismal aging and understanding adipose remodelling contributes to discovering novel anti-aging targets. Glutathione peroxidase 3 (GPx3), a critical endogenous antioxidant enzyme, is diminished in the subcutaneous adipose tissue (sWAT) with white adipose expansion. Based on the active role of the antioxidant system in counteracting aging, we investigated the involvement of GPx3 in adipose senescence. We determined that knockdown of GPx3 in adipose tissue by adeno-associated viruses impaired mitochondrial function in mice, increased susceptibility to obesity, and exacerbated adipose tissue senescence. Impairment of GPx3 may cause mitochondrial dysfunction through inner mitochondrial membrane disruption. Adipose reshaping management (cold stimulation and intermittent diet) counteracted the aging of tissues, with an increase in GPx3 expression. Overall metabolic improvement induced by cold stimulation was partially attenuated when GPx3 was depleted. GPx3 may be involved in adipose browning by interacting with UCP1, and GPx3 may be a limiting factor for intracellular reactive oxygen species (ROS) accumulation during stem cell browning. Collectively, these findings emphasise the importance of restoring the imbalanced redox state in adipose tissue to counteract aging and that GPx3 may be a potential target for maintaining mitochondrial homeostasis and longevity.
    Keywords:  Adipose tissue; Anti-Senescence; Glutathione peroxidase 3; Mitochondrial
    DOI:  https://doi.org/10.1016/j.redox.2024.103365
  11. Free Radic Biol Med. 2024 Sep 24. pii: S0891-5849(24)00683-X. [Epub ahead of print]
    NAD+ homeostasis and its role in exercise adaptation: A comprehensive review.
    Zhi Jiang, Xun Luo, Chong Han, Yuan-Yuan Qin, Shan-Yao Pan, Zheng-Hong Qin, Jie Bao, Li Luo.
      Nicotinamide adenine dinucleotide (NAD+) is a crucial coenzyme involved in catalyzing cellular redox reactions and serving as a substrate for NAD+-dependent enzymes. It plays a vital role in maintaining tissue homeostasis and promoting healthy aging. Exercise, a well-established and cost-effective method for enhancing health, can influence various pathways related to NAD+ metabolism. Strategies such as supplementing NAD+ precursors, modulating NAD+ synthesis enzymes, or inhibiting enzymes that consume NAD+ can help restore NAD+ balance and improve exercise performance. Various overlapping signaling pathways are known to play a crucial role in the beneficial effects of both NAD+ and exercise on enhancing health and slowing aging process. Studies indicate that a combined strategy of exercise and NAD+ supplementation could synergistically enhance athletic capacity. This review provides an overview of current research on the interactions between exercise and the NAD+ network, underscoring the significance of NAD+ homeostasis in exercise performance. It also offers insights into enhancing exercise capacity and improving aging-related diseases through the optimal use of exercise interventions and NAD+ supplementation methods.
    Keywords:  NAD+; aging; exercise; metabolism
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.09.036
  12. CRISPR J. 2024 Sep 26.
    Genome Editing Therapy for the Blood: Ex Vivo Success and In Vivo Prospects.
    Christy A George, Srishti U Sahu, Lorena de Oñate, Bruno Solano de Freitas Souza, Ross C Wilson.
      Hematopoietic stem cells (HSCs) provide the body with a continuous supply of healthy, functional blood cells. In patients with hematopoietic malignancies, immunodeficiencies, lysosomal storage disorders, and hemoglobinopathies, therapeutic genome editing offers hope for corrective intervention, with even modest editing efficiencies likely to provide clinical benefit. Engineered white blood cells, such as T cells, can be applied therapeutically to address monogenic disorders of the immune system, HIV infection, or cancer. The versatility of CRISPR-based tools allows countless new medical interventions for diseases of the blood, and rapid ex vivo success has been demonstrated in hemoglobinopathies via transplantation of the patient's HSCs following genome editing in a laboratory setting. Here we review recent advances in therapeutic genome editing of HSCs and T cells, focusing on the progress in ex vivo contexts, the promise of improved access via in vivo delivery, as well as the ongoing preclinical efforts that may enable the transition from ex vivo to in vivo administration. We discuss the challenges, limitations, and future prospects of this rapidly developing field, which may one day establish CRISPR as the standard of care for some diseases affecting the blood.
    DOI:  https://doi.org/10.1089/crispr.2024.0036
  13. Aging Cell. 2024 Sep 19. e14335
    E5 treatment showing improved health-span and lifespan in old Sprague Dawley rats.
    Kavita Singh, Shraddha I Khairnar, Akshay Sanghavi, Tanuja T Yadav, Neha Gupta, Jay Arora, Harold L Katcher.
      Aging and, in particular, the emergence of age-related disorders is associated with tissue dysfunction and macromolecular damage, some of which can be attributable to accumulated oxidative damage. In the current study, we determine the potential of 'plasma-derived fraction (E5)' for cellular rejuvenation and extending the lifespan of Sprague Dawley (SD) rats. This is a unique study wherein we have used 24-month-old rats and monitored them until the end of their lifespan with and without E5 treatment. In the present investigation, the SD rats were separated into two groups old control group and the treatment group (n = 8). The treatment group received four injections of E5 every alternate day for 8 days, and eight injections every alternate day for 16 days. Body weight, grip strength, cytokines, and biochemical markers were measured for more than 400 days of the study. Clinical observation, necropsy, and histology were performed. The E5 treatment exhibited great potential by showing significantly improved grip strength, remarkably decreased pro-inflammatory markers of chronic inflammation and oxidative stress, as well as biomarkers for vital organs (BUN, SGPT, SGOT, and triglycerides), and increased anti-oxidant levels. Clinical examinations, necropsies, and histopathology revealed that the animals treated with the E5 had normal cellular structure and architecture. In conclusion, this unique 'plasma-derived exosome' treatment (E5) alone is adequate to improve the health-span and extend the lifespan of the old SD rats significantly.
    Keywords:  E5; cytokines; health‐span; lifespan; longevity; rejuvenation
    DOI:  https://doi.org/10.1111/acel.14335
  14. World J Exp Med. 2024 Sep 20. 14(3): 97233
    Anti-aging based on stem cell therapy: A scoping review.
    Nassar El Assaad, Alain Chebly, Rawad Salame, Robert Achkar, Nour Bou Atme, Khalil Akouch, Paul Rafoul, Colette Hanna, Samer Abou Zeid, Marwan Ghosn, Charbel Khalil.
      Stem cells are present in the tissues and organs and remain in a quiescent and undifferentiated state until it is physiologically necessary to produce new descendant cells. Due to their multipotency property, mesenchymal stem cells have attracted considerable attention worldwide due to their immunomodulation and therapeutic function in tissue regeneration. Stem cells secrete components such as paracrine factors, extracellular vesicles, and exosomes which have been shown to have anti-inflammatory, anti-aging, reconstruction and wound healing potentials in many in vitro and in vivo models. The pluripotency and immunomodulatory features of stem cells could potentially be an effective tool in cell therapy and tissue repair. Aging affects the capacity for self-renewal and differentiation of stem cells, decreasing the potential for regeneration and the loss of optimal functions in organisms over time. Current progress in the field of cellular therapy and regenerative medicine has facilitated the evolution of particular guidelines and quality control approaches, which eventually lead to clinical trials. Cell therapy could potentially be one of the most promising therapies to control aging due to the fact that single stem cell transplantation can regenerate or substitute the injured tissue. To understand the involvement of stem cells not only in tissue maintenance and disease but also in the control of aging it is important to know and identify their properties, functions, and regulation in vivo, which are addressed in this review.
    Keywords:  Anti-aging; Mesenchymal stem cell; Regenerative medicine; Stem cell therapy; Telomerase
    DOI:  https://doi.org/10.5493/wjem.v14.i3.97233
  15. FEBS J. 2024 Sep 26.
    Senescence in the ageing skin: a new focus on mTORC1 and the lysosome.
    Phineas Smith, Bernadette Carroll.
      Ageing is defined as the progressive loss of tissue function and regenerative capacity and is caused by both intrinsic factors i.e. the natural accumulation of damage, and extrinsic factors i.e. damage from environmental stressors. Cellular senescence, in brief, is an irreversible exit from the cell cycle that occurs primarily in response to excessive cellular damage, such as from ultraviolet (UV) exposure and oxidative stress, and it has been comprehensively demonstrated to contribute to tissue and organismal ageing. In this review, we will focus on the skin, an organ which acts as an essential protective barrier against injury, insults, and infection. We will explore the evidence for the existence and contribution of cellular senescence to skin ageing. We discuss the known molecular mechanisms driving senescence in the skin, with a focus on the dysregulation of the master growth regulator, mechanistic Target of Rapamycin Complex 1 (mTORC1). We explore the interplay of dysregulated mTORC1 with lysosomes and how they contribute to senescence phenotypes.
    Keywords:  ageing; lysosome; mTORC1; senescence; skin
    DOI:  https://doi.org/10.1111/febs.17281
  16. Nat Commun. 2024 Sep 27. 15(1): 8358
    Programmable editing of primary MicroRNA switches stem cell differentiation and improves tissue regeneration.
    Vu Anh Truong, Yu-Han Chang, Thuc Quyen Dang, Yi Tu, Jui Tu, Chin-Wei Chang, Yi-Hao Chang, Guei-Sheung Liu, Yu-Chen Hu.
      Programmable RNA editing is harnessed for modifying mRNA. Besides mRNA, miRNA also regulates numerous biological activities, but current RNA editors have yet to be exploited for miRNA manipulation. To engineer primary miRNA (pri-miRNA), the miRNA precursor, we present a customizable editor REPRESS (RNA Editing of Pri-miRNA for Efficient Suppression of miRNA) and characterize critical parameters. The optimized REPRESS is distinct from other mRNA editing tools in design rationale, hence enabling editing of pri-miRNAs that are not editable by other RNA editing systems. We edit various pri-miRNAs in different cells including adipose-derived stem cells (ASCs), hence attenuating mature miRNA levels without disturbing host gene expression. We further develop an improved REPRESS (iREPRESS) that enhances and prolongs pri-miR-21 editing for at least 10 days, with minimal perturbation of transcriptome and miRNAome. iREPRESS reprograms ASCs differentiation, promotes in vitro cartilage formation and augments calvarial bone regeneration in rats, thus implicating its potentials for engineering miRNA and applications such as stem cell reprogramming and tissue regeneration.
    DOI:  https://doi.org/10.1038/s41467-024-52707-6
  17. Sports Med Health Sci. 2024 Dec;6(4): 302-314
    Exercise and nutrition benefit skeletal muscle: From influence factor and intervention strategy to molecular mechanism.
    Lili Feng, Bowen Li, Su Sean Yong, Xiaonan Wu, Zhenjun Tian.
      Sarcopenia is a progressive systemic skeletal muscle disease induced by various physiological and pathological factors, including aging, malnutrition, denervation, and cardiovascular diseases, manifesting as the decline of skeletal muscle mass and function. Both exercise and nutrition produce beneficial effects on skeletal muscle growth and are viewed as feasible strategies to prevent sarcopenia. Mechanisms involve regulating blood flow, oxidative stress, inflammation, apoptosis, protein synthesis and degradation, and satellite cell activation through exerkines and gut microbiomes. In this review, we summarized and discussed the latest progress and future development of the above mechanisms for providing a theoretical basis and ideas for the prevention and treatment of sarcopenia.
    Keywords:  Diet; Exercise; Exerkines; Sarcopenia; Satellite cells; Signaling pathway; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.smhs.2024.02.004
  18. Adv Sci (Weinh). 2024 Sep 27. e2406670
    A Novel Metabolomic Aging Clock Predicting Health Outcomes and Its Genetic and Modifiable Factors.
    Xueqing Jia, Jiayao Fan, Xucheng Wu, Xingqi Cao, Lina Ma, Zeinab Abdelrahman, Fei Zhao, Haitao Zhu, Daniele Bizzarri, Erik B van den Akker, P Eline Slagboom, Joris Deelen, Dan Zhou, Zuyun Liu.
      Existing metabolomic clocks exhibit deficiencies in capturing the heterogeneous aging rates among individuals with the same chronological age. Yet, the modifiable and non-modifiable factors in metabolomic aging have not been systematically studied. Here, a new aging measure-MetaboAgeMort-is developed using metabolomic profiles from 239,291 UK Biobank participants for 10-year all-cause mortality prediction. The MetaboAgeMort showed significant associations with all-cause mortality, cause-specific mortality, and diverse incident diseases. Adding MetaboAgeMort to a conventional risk factors model improved the predictive ability of 10-year mortality. A total of 99 modifiable factors across seven categories are identified for MetaboAgeMort. Among these, 16 factors representing pulmonary function, body composition, socioeconomic status, dietary quality, smoking status, alcohol intake, and disease status showed quantitatively stronger associations. The genetic analyses revealed 99 genomic risk loci and 271 genes associated with MetaboAgeMort. The tissue-enrichment analysis showed significant enrichment in liver. While the external validation of the MetaboAgeMort is required, this study illuminates heterogeneous metabolomic aging across the same age, providing avenues for identifying high-risk individuals, developing anti-aging therapies, and personalizing interventions, thus promoting healthy aging and longevity.
    Keywords:  aging; biological age; genetic determinant; metabolomic; modifiable factor; mortality
    DOI:  https://doi.org/10.1002/advs.202406670
  19. J Zhejiang Univ Sci B. 2024 Sep 15. pii: 1673-1581(2024)09-0723-13. [Epub ahead of print]25(9): 723-735
    Research advances in the function and anti-aging effects of nicotinamide mononucleotide.
    Min Wang, Yuan Cao, Yun Li, Lu Wang, Yuyan Liu, Zihui Deng, Lianrong Zhu, Hongjun Kang.
      Aging and age-related ailments have emerged as critical challenges and great burdens within the global contemporary society. Addressing these concerns is an imperative task, with the aims of postponing the aging process and finding effective treatments for age-related degenerative diseases. Recent investigations have highlighted the significant roles of nicotinamide adenine dinucleotide (NAD+) in the realm of anti-aging. It has been empirically evidenced that supplementation with nicotinamide mononucleotide (NMN) can elevate NAD+ levels in the body, thereby ameliorating certain age-related degenerative diseases. The principal anti-aging mechanisms of NMN essentially lie in its impact on cellular energy metabolism, inhibition of cell apoptosis, modulation of immune function, and preservation of genomic stability, which collectively contribute to the deferral of the aging process. This paper critically reviews and evaluates existing research on the anti-aging mechanisms of NMN, elucidates the inherent limitations of current research, and proposes novel avenues for anti-aging investigations.
    Keywords:  Anti-aging; Apoptosis; DNA repair; Energy metabolism; Nicotinamide mononucleotide (NMN)
    DOI:  https://doi.org/10.1631/jzus.B2300886
  20. Methods Mol Biol. 2024 Sep 25.
    Tubular Aggregates as a Marker of Aging in Skeletal Muscle.
    Felipe Tadeu Galante Rocha de Vasconcelos, Brandow Willy Souza, Lucas Santos Souza, Mariz Vainzof.
      Tubular aggregates (TA) are skeletal muscle structures that arise from the progressive accumulation of sarcoplasmic reticulum proteins, mainly with aging. Muscle regeneration plays a role in TA formation. TA quantification may aid in the evaluation of muscle aging and genetic muscle degeneration. TA form over time, appears in aging in normal murine muscles. TA reduction in injured conditions may be due to the degeneration-regeneration process in muscles, with loss of damaged muscle fibers and formation of new fibers that do not present protein aggregation. These new regenerated fibers do not improve the function capacity of the aged muscle. Here, we present a methodology for labeling and identifying tubular aggregates in muscle fibers and also the standardization of its quantification.
    Keywords:  Aging; Mouse; Muscle regeneration; Muscular dystrophies; Neuromuscular disease; Tubular aggregates
    DOI:  https://doi.org/10.1007/7651_2024_567
  21. Redox Biol. 2024 Sep 19. pii: S2213-2317(24)00341-0. [Epub ahead of print]77 103363
    Lycopene alleviates age-related cognitive deficit via activating liver-brain fibroblast growth factor-21 signalling.
    Jia Wang, Lu Li, Li Li, Yuqi Shen, Fubin Qiu.
      Brain function is linked with many peripheral tissues, including the liver, where hepatic fibroblast growth factor 21 (FGF21) mediates communication between the liver and brain. Lycopene (LYC), a naturally occurring carotenoid, posses multiple health-promoting properties, including neuroprotective function. Here, we investigated the effects of LYC on age-related memory impairment and the relative contribution of liver-brain FGF21 signaling in these process. The results showed that after treatment with LYC for 3 months, brain aging and age-related cognitive deficits were effectively managed. In addition, LYC ameliorated neuronal degeneration, mitochondrial dysfunction and synaptic damage, and promoted synaptic vesicle fusion in 18-month-old mice. Notably, LYC activated liver-brain FGF21 signalling in aging mice. Whereas all these central effects of LYC were negated by blocking FGF21 via i. v. injection of adeno-associated virus in aging mice. Furthermore, recombinant FGF21 elevated mitochondrial ATP levels and enhanced synaptic vesicle fusion in mouse hippocampal HT-22 cells, which promoted neurotransmitter release. Additionally, we co-cultured hepatocytes and neurons in Transwell and found that LYC enhanced hepatocytes' support for neurons. This support included improved cell senescence, enhanced mitochondrial function, and increased axon length in co-cultured neurons. In conclusion, LYC protects against age-related cognitive deficit, partly explained by activating liver-brain FGF21 signalling, hence promoting neurotransmitters release via increasing mitochondrial ATP levels and enhancing synaptic vesicle fusion. These findings revealed that FGF21 could be a potential therapeutical target in nutritional intervention strategies to improve cognitive damage caused by aging and age-related neurodegenerative diseases.
    Keywords:  Aging; Liver-brain FGF21 signalling; Lycopene; Neurotransmitters; Synaptic vesicle fusion
    DOI:  https://doi.org/10.1016/j.redox.2024.103363
  22. Biol Rev Camb Philos Soc. 2024 Sep 26.
    Protection of the genome and the central exome by peripheral non-coding DNA against DNA damage in health, ageing and age-related diseases.
    Guo-Hua Qiu, Mingjun Fu, Xintian Zheng, Cuiqin Huang.
      DNA in eukaryotic genomes is under constant assault from both exogenous and endogenous sources, leading to DNA damage, which is considered a major molecular driver of ageing. Fortunately, the genome and the central exome are safeguarded against these attacks by abundant peripheral non-coding DNA. Non-coding DNA codes for small non-coding RNAs that inactivate foreign nucleic acids in the cytoplasm and physically blocks these attacks in the nucleus. Damage to non-coding DNA produced during such blockage is removed in the form of extrachromosomal circular DNA (eccDNA) through nucleic pore complexes. Consequently, non-coding DNA serves as a line of defence for the exome against DNA damage. The total amount of non-coding DNA/heterochromatin declines with age, resulting in a decrease in both physical blockage and eccDNA exclusion, and thus an increase in the accumulation of DNA damage in the nucleus during ageing and in age-related diseases. Here, we summarize recent evidence supporting a protective role of non-coding DNA in healthy and pathological states and argue that DNA damage is the proximate cause of ageing and age-related genetic diseases. Strategies aimed at strengthening the protective role of non-coding DNA/heterochromatin could potentially offer better systematic protection for the dynamic genome and the exome against diverse assaults, reduce the burden of DNA damage to the exome, and thus slow ageing, counteract age-related genetic diseases and promote a healthier life for individuals.
    Keywords:  DNA damage; ageing; age‐related diseases; eccDNA; exome; genome defence; non‐coding DNA; nucleic pore complex
    DOI:  https://doi.org/10.1111/brv.13151
  23. J Dent Res. 2024 Sep 23. 220345241266775
    ALKBH5 Regulates Osteogenic Differentiation via the lncRNA/mRNA Complex.
    Y Song, H Gao, Y Pan, Y Gu, W Sun, Y Wang, J Liu.
      Human adipose-derived stem cells (hASCs) are commonly used in bone tissue regeneration. The N6-methyladenosine (m6A) modification has emerged as a novel regulatory mechanism for gene expression, playing a critical role in osteogenic differentiation of stem cells. However, the precise role and mechanism of alkylation repair homolog 5 (ALKBH5) in hASC osteogenesis remain incompletely elucidated and warrant further investigation. Herein, we employed methylated RNA immunoprecipitation sequencing, RNA sequencing, and weighted gene coexpression network analysis to identify a key long noncoding RNA (lncRNA) in hASCs: lncRNA AK311120. Functional experiments demonstrated that lnc-AK311120 promoted the osteogenic differentiation of hASCs, while a mutation at the m6A central site A of lnc-AK311120 was found to decrease the level of m6A modification. The osteogenic effect of ALKBH5 was confirmed both in vitro and in vivo using a mandibular defect model in nude mice. Subsequent investigations revealed that knockdown of ALKBH5 resulted in a significant increase in the m6A modification level of lnc-AK311120, accompanied by a downregulation in the expression level of lnc-AK311120. Additional rescue experiments demonstrated that overexpression of lnc-AK311120 could restore the phenotype after ALKBH5 knockdown. We observed that AK311120 interacted with the RNA-binding proteins DExH-Box helicase 9 (DHX9) and YTH domain containing 2 (YTHDC2) to form a ternary complex, while mitogen-activated protein kinase kinase 7 (MAP2K7) served as the shared downstream target gene of DHX9 and YTHDC2. Knockdown of AK311120 led to a reduction in the binding affinity between DHX9/YTHDC2 and the target gene MAP2K7. Furthermore, ALKBH5 facilitated the translation of MAP2K7 and activated the downstream JNK signaling pathway through the AK311120-DHX9-YTHDC2 complex, without affecting its messenger RNA level. Collectively, we have investigated the regulatory effect and mechanism of ALKBH5-mediated demethylation of lncRNA in hASC osteogenesis for the first time, offering a promising approach for bone tissue engineering.
    Keywords:  cell differentiation; epigentic; gene expression; growth/development; osteogenesis; stem cell
    DOI:  https://doi.org/10.1177/00220345241266775
  24. Sci China Life Sci. 2024 Sep 24.
    Tauroursodeoxycholic acid targets HSP90 to promote protein homeostasis and extends healthy lifespan.
    Jia-Yu Liu, Yao Wang, Yue Guo, Run-Qi Zheng, Yun-Ying Wang, Yan-Yan Shen, Yan-Hong Liu, Ai-Ping Cao, Rui-Bo Wang, Bo-Yang Xie, Shuai Jiang, Qiu-Ying Han, Jing Chen, Fang-Ting Dong, Kun He, Na Wang, Xin Pan, Tao Li, Tao Zhou, Ai-Ling Li, Qing Xia, Wei-Na Zhang.
      As the elderly population expands, the pursuit of therapeutics to reduce morbidity and extend lifespan has become increasingly crucial. As an FDA-approved drug for chronic cholestatic liver diseases, tauroursodeoxycholic acid (TUDCA), a natural bile acid, offers additional health benefits beyond liver protection. Here, we show that TUDCA extends the lifespan and healthspan of C. elegans. Importantly, oral supplementation of TUDCA improves fitness in old mice, including clinically relevant phenotypes, exercise capacity and cognitive function. Consistently, TUDCA treatment drives broad transcriptional changes correlated with anti-aging characteristics. Mechanistically, we discover that TUDCA targets the chaperone HSP90 to promote its protein refolding activity. This collaboration further alleviates aging-induced endoplasmic reticulum (ER) stress and facilitates protein homeostasis, thus offering resistance to aging. In summary, our findings uncover new molecular links between an endogenous metabolite and protein homeostasis, and propose a novel anti-aging strategy that could improve both lifespan and healthspan.
    Keywords:  healthspan; lifespan; protein homeostasis; tauroursodeoxycholic acid
    DOI:  https://doi.org/10.1007/s11427-024-2717-6
  25. Altern Ther Health Med. 2024 Sep 24. pii: AT11451. [Epub ahead of print]
    The Glutathione Theory of Aging.
    Ross Pelton.
      The Glutathione Theory of Aging reviews the multiple biological functions of glutathione, including its status as the Master Antioxidant, and its role as a key regulator of detoxification, immune function and anti-viral activity. Sub-optimal glutathione levels are common because many diet, lifestyle, and environmental factors contribute to glutathione depletion, and the body's ability to synthesize glutathione declines as people age. Studies reveal that most age-related chronic degenerative diseases are associated with low glutathione levels. This article also introduces people to Lactobacillus fermentum ME-3, which is a unique strain of probiotic bacteria thar synthesizes glutathione. Boosting glutathione levels is an important proactive step people can take to promote good health and achieve healthy longevity.
  26. Ageing Res Rev. 2024 Sep 25. pii: S1568-1637(24)00330-1. [Epub ahead of print] 102512
    The impact of short-lived controls on the interpretation of lifespan experiments and progress in geroscience - through the lens of the "900-day rule".
    Kamil Pabis, Diogo Barardo, Jan Gruber, Olga Sirbu, Marco Malavolta, Kumar Selvarajoo, Matt Kaeberlein, Brian K Kennedy.
      Although lifespan extension remains the gold standard for assessing interventions proposed to impact the biology of aging, there are important limitations to this approach. Our reanalysis of lifespan studies from multiple sources suggests that short lifespans in the control group exaggerate the relative efficacy of putative longevity interventions. Results may be exaggerated due to statistical effects (e.g. regression to the mean) or other factors. Moreover, due to the high cost and long timeframes of mouse studies, it is rare that a particular longevity intervention will be independently replicated by multiple groups. To facilitate identification of successful interventions, we propose an alternative approach particularly suitable for well-characterized inbred and HET3 mice. The level of confidence we can have in an intervention is proportional to the degree of lifespan extension above the strain- and species-specific upper limit of lifespan, which we can estimate from comparison to historical controls. In the absence of independent replication, a putative mouse longevity intervention should only be considered with high confidence when control median lifespans are close to 900 days or if the final lifespan of the treated group is considerably above 900 days. Using this "900-day rule" we identified several candidate interventions from the literature that merit follow-up studies.
    Keywords:  Interventions Testing Program; caloric restriction; meta-analysis; mouse husbandry; systematic review
    DOI:  https://doi.org/10.1016/j.arr.2024.102512
  27. Exp Eye Res. 2024 Sep 18. pii: S0014-4835(24)00325-7. [Epub ahead of print]248 110103
    Estrogen, via ESR2 receptor, prevents oxidative stress-induced Müller cell death and stimulates FGF2 production independently of NRF2, attenuating retinal degeneration.
    Hiroshi Tawarayama, Keiko Uchida, Hirokazu Hasegawa, Masaaki Yoshida, Maki Inoue-Yanagimachi, Wataru Sato, Noriko Himori, Masayuki Yamamoto, Toru Nakazawa.
      In this study, we aimed to investigate the effects of the deficient antioxidative gene, nuclear factor-erythroid 2-related factor 2 (Nrf2), on 17β-estradiol (E2)-mediated oxidative stress response, with a specific focus on growth factor production and cell death in Müller cells and retinal tissue. Administration of hydrogen peroxide (H2O2) reduced the viability of Müller cells derived from Nrf2 wild-type (WT) and knockout (KO) mice. However, this effect was more significant in the KO cells than in the WT cells. Pretreatment with E2 inhibited H2O2-induced cell death in both Nrf2 WT and KO Müller cell genotypes. Small interfering RNA-mediated gene silencing of estrogen receptor 2 (Esr2) attenuated the cell survival-promoting activity of E2 in Nrf2 KO Müller cells, while other identified estrogen receptors, Esr1 or G protein-coupled estrogen receptor 1 (Gper1), had no effect. Western blotting revealed higher ESR2 expression levels in Nrf2 KO cells than in WT Müller cells. Conditioned media from E2-and H2O2-treated Nrf2 WT or KO Müller cells enhanced the dissociated retinal cell viability compared with H2O2-treated cells. Both quantitative reverse-transcription polymerase chain reaction assay (qRT-PCR) and enzyme-linked immunosorbent assay exhibited a significant increase in fibroblast growth factor 2 (FGF2) expression levels in E2-and H2O2-treated Nrf2 WT and KO Müller cells compared to those in E2-treated cells. In vivo, administration of N-methyl-N-nitrosourea (MNU) reduced the thickness and cell density of the outer nuclear layer (ONL) in Nrf2 KO mice and enhanced the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells in the ONL. However, E2 administration attenuated these defects in MNU-treated mice. Concomitant administration of MNU and E2 enhanced FGF2 protein levels in retinal lysates of Nrf2 KO mice. In conclusion, E2 demonstrated a significant role in preventing oxidative stress-induced retinal cell death by stimulating FGF2 production in Müller cells, independent of the Nrf2 gene. Based on these findings, we anticipate that exogenous administration of estrogens or ESR2-selective agonists could aid in treating patients with oxidative stress-related retinal degenerative diseases such as age-related macular degeneration and retinitis pigmentosa.
    Keywords:  Estrogen; FGF2; Müller glia; Oxidative stress; Photoreceptors
    DOI:  https://doi.org/10.1016/j.exer.2024.110103
  28. J Inflamm Res. 2024 ;17 6635-6643
    Inflammatory Memory in Epidermal Stem Cells - A New Strategy for Recurrent Inflammatory Skin Diseases.
    Qian Gao, Ping-Sheng Hao.
      The ability of the skin to "remember" has been a potential mechanism for studying recurrent skin diseases. While it has been thought that the ability to retain past encounters is the prerogative of immune cells, it has recently been discovered that skin tissue stem cells can also take on this task. Epithelial stem cells undergoing inflammation retain their "memory" through epigenetic reprogramming and exhibit rapid epithelialization and epidermal proliferation upon secondary stimulation. This is a non-specific memory modality independent of conventional immune memory, in which histone modifications (acetylation and methylation) and specific transcription factors (AP-1 and STAT3) are involved in the establishment of inflammatory memories, and AIM2/Caspase-1/IL-1β mainly performs the rapid effects of memory. This finding is intriguing for addressing recurrent inflammatory skin diseases, which may explain the fixed-site recurrence of inflammatory skin diseases and develop new therapeutic strategies in the future. However, more research is still needed to decipher the mysteries of memory.
    Keywords:  epigenetics; inflammatory memory; recurrent inflammatory skin diseases; skin tissue stem cells
    DOI:  https://doi.org/10.2147/JIR.S478987
  29. Nanoscale. 2024 Sep 26.
    A biocompatible polydopamine platform for targeted delivery of nicotinamide mononucleotide and boosting NAD+ levels in the brain.
    Xiaoli Cai, Yuteng Huang, Ting Wang, Ziping Wang, Lei Jiao, Jingling Liao, Li Zhou, Chengzhou Zhu, Shuang Rong.
      Nicotinamide mononucleotide (NMN), a precursor of the coenzyme nicotinamide adenine dinucleotide (NAD+), has gained wide attention as an anti-aging agent, which plays a significant role in intracellular redox reactions. However, its effectiveness is limited by easy metabolism in the liver and subsequent excretion as nicotinamide, resulting in low bioavailability, particularly in the brain. Additionally, the blood-brain barrier (BBB) further hinders NMN supply to the brain, compromising its potential anti-aging effects. Herein, we developed a biocompatible polydopamine (PDA) platform to deliver NMN for boosting NAD+ levels in the brain for the first time. The lactoferrin (Lf) ligand was covalently attached to the PDA spheres to improve BBB transport efficiency. The resultant PDA-based system, referred to as PDA-Lf-NMN, not only exhibited superior BBB penetration ability but also improved the utilization rate of brain NMN in elevating NAD+ levels compared to NMN alone for both young (3 months) and old (21 months) mice. Moreover, after the old mice were treated with low-dose PDA-Lf-NMN (8 mg kg-1 day-1), they exhibited improved spatial cognition. Importantly, these nanomedicines did not induce any cellular necrosis or apoptosis. It provides a promising avenue for delivering NMN specifically to the brain, boosting NAD+ levels for promoting longevity and treating brain aging-related diseases.
    DOI:  https://doi.org/10.1039/d4nr02934h
  30. Aging Dis. 2024 Sep 01.
    Senescence- and Immunity-Related Changes in the Central Nervous System: A Comprehensive Review.
    Haiwen Feng, Junjin Li, Hongda Wang, Zhijian Wei, Shiqing Feng.
      Senescence is a cellular state characterized by an irreversible halt in the cell cycle, accompanied by alterations in cell morphology, function, and secretion. Senescent cells release a plethora of inflammatory and growth factors, extracellular matrix proteins, and other bioactive substances, collectively known as the senescence-associated secretory phenotype (SASP). These excreted substances serve as crucial mediators of senescent tissues, while the secretion of SASP by senescent neurons and glial cells in the central nervous system modulates the activity of immune cells. Senescent immune cells also influence the physiological activities of various cells in the central nervous system. Further, the interaction between cellular senescence and immune regulation collectively affects the physiological and pathological processes of the central nervous system. Herein, we explore the role of senescence in the physiological and pathological processes underlying embryonic development, aging, degeneration, and injury of the central nervous system, through the immune response. Further, we elucidate the role of senescence in the physiological and pathological processes of the central nervous system, proposing a new theoretical foundation for treating central nervous system diseases.
    DOI:  https://doi.org/10.14336/AD.2024.0755
  31. bioRxiv. 2024 Sep 15. pii: 2024.09.14.613027. [Epub ahead of print]
    NuRD chromatin remodeling is required to repair exogenous DSBs in the Caenorhabditis elegans germline.
    Deepshikha Ananthaswamy, Kelin Funes, Thiago Borges, Scott Roques, Nina Fassnacht, Sereen El Jamal, Paula M Checchi, Teresa Wei-Sy Lee.
      Organisms rely on coordinated networks of DNA repair pathways to protect genomes against toxic double-strand breaks (DSBs), particularly in germ cells. All repair mechanisms must successfully negotiate the local chromatin environment in order to access DNA. For example, nucleosomes can be repositioned by the highly conserved Nucleosome Remodeling and Deacetylase (NuRD) complex. In Caenorhabditis elegans, NuRD functions in the germline to repair DSBs - the loss of NuRD's ATPase subunit, LET-418/CHD4, prevents DSB resolution and therefore reduces fertility. In this study, we challenge germlines with exogenous DNA damage to better understand NuRD's role in repairing DSBs. We find that let-418 mutants are hypersensitive to cisplatin and hydroxyurea: exposure to either mutagen impedes DSB repair, generates aneuploid oocytes, and severely reduces fertility and embryonic survival. These defects resemble those seen when the Fanconi anemia (FA) DNA repair pathway is compromised, and we find that LET-418's activity is epistatic to that of the FA component FCD-2/FANCD2. We propose a model in which NuRD is recruited to the site of DNA lesions to remodel chromatin and allow access for FA pathway components. Together, these results implicate NuRD in the repair of both endogenous DSBs and exogenous DNA lesions to preserve genome integrity in developing germ cells.
    Keywords:  DNA repair; FCD-2/FANCD2; LET-418/CHD4; NuRD (nucleosome remodeling and deacetylase complex); germline
    DOI:  https://doi.org/10.1101/2024.09.14.613027
  32. bioRxiv. 2024 Sep 15. pii: 2024.09.13.612919. [Epub ahead of print]
    Multifaceted roles of H2B mono-ubiquitylation in D-loop metabolism during homologous recombination repair.
    Shih-Hsun Hung, Yuan Liang, Wolf-Dietrich Heyer.
      Repairing DNA double-strand breaks is crucial for maintaining genome integrity, which occurs primarily through homologous recombination (HR) in S. cerevisiae. Nucleosomes, composed of DNA wrapped around a histone octamer, present a natural barrier to end-resection to initiate HR, but the impact on the downstream HR steps of homology search, DNA strand invasion and repair synthesis remain to be determined. Displacement loops (D-loops) play a pivotal role in HR, yet the influence of chromatin dynamics on D-loop metabolism remains unclear. Using the physical D-loop capture (DLC) and D-loop extension (DLE) assays to track HR intermediates, we employed genetic analysis to reveal that H2B mono-ubiquitylation (H2Bubi) affects multiple steps during HR repair. We infer that H2Bubi modulates chromatin structure, not only promoting histone degradation for nascent D-loop formation but also stabilizing extended D-loops through nucleosome assembly. Furthermore, H2Bubi regulates DNA resection via Rad9 recruitment to suppress a feedback control mechanism that dampens D-loop formation and extension at hyper-resected ends. Through physical and genetic assays to determine repair outcomes, we demonstrate that H2Bubi plays a crucial role in preventing break-induced replication and thus promoting genomic stability.
    Highlights: H2Bubi is epistatic to H2A.Z and INO80 in promoting homology search and D-loop formationH2Bubi stabilizes extended D-loopExcessive resection counteracts D-loop formation and extensionH2Bubi promotes crossover events and limits the frequency of break-induced replication outcomes in HR repair.
    DOI:  https://doi.org/10.1101/2024.09.13.612919
  33. Mol Neurobiol. 2024 Sep 23.
    Delta Opioid Peptide [d-Ala2, d-Leu5]-Enkephalin Improves Physical and Cognitive Function and Increases Lifespan in Aged Female Mice.
    Lixia Huo, Hongquan Zhang, Chengwu Tang, Ge Cui, Tao Xue, Huihui Guo, Fandi Yao, Wei Zhang, Wenming Feng.
      In this study, we explored the potential application of [d-Ala2, d-Leu5]-enkephalin (DADLE) in anti-ageing field in response to the trend of increasing global population ageing. We aimed to reveal experimentally whether DADLE can positively affect the lifespan and health of aged mammals through its unique anti-inflammatory or metabolic mechanisms. Forty-two female C57/BL6J mice aged 18 months were intraperitoneally injected with DADLE or normal saline for 2 months. Cognitive and motor functions were assessed using a water maze and treadmill stress test, respectively. The expressions of P16INK4A, Lamin B1 and sirtuin 1 were observed in the hippocampus and heart. The level of pro-inflammatory cytokines in the serum was measured by enzyme-linked immunosorbent assay. The telomere length of the mice was determined using the polymerase chain reaction method. Transcriptome analysis of 6-month-old female C57BL/6 J mice brains and hearts was assessed for body weight effects. Supplementation of exogenous DADLE to aged mice has demonstrated significant benefits, including improved motor function, enhanced cognitive performance and significantly extended lifespan. DADLE treatment resulted in a substantial increase in anti-ageing markers and a corresponding decrease in pro-ageing markers in the heart and brain of these mice. DADLE attenuated age-related inflammation, as evidenced by reductions in serum pro-inflammatory cytokines and inflammatory cell infiltration in tissues. Furthermore, DADLE supplementation significantly prolonged relative telomere length in aged female mice, suggesting a potential mechanism for its anti-ageing effects. Transcriptome analysis revealed that immune response and cellular signalling pathways are intricately involved in the protective effects of DADLE in aged mice, providing further insights into its mechanism of action. Inflammatory reaction may be improved by DADLE by regulating the infiltration of inflammatory cells in the liver and kidney and regulating the cognitive function of the brain and the ageing of the heart in mice.
    Keywords:  Aged Mice; Cognitive Function; Enkephalin; Lifespan; Motor Function
    DOI:  https://doi.org/10.1007/s12035-024-04503-y
  34. Med Acupunct. 2024 Aug;36(4): 173-177
    Getting to Know the Effect Theory of Traditional Pediatric Tuina in the View of Modern Medicine in Three Minor Perspectives.
    Shu-Cheng Chen, Qin-Wei Fu, Qin-Xiu Zhang, Wing-Fai Yeung.
      Pediatric tuina is a traditional Chinese medicine (TCM) modality that is well-accepted and applied in China currently. As a traditional medicine, it is based on TCM theories and clinical experience. In the TCM area, the "self-healing" system of the human body includes two aspects: self-regulation and adaptation, through which pediatric tuina could rectify dysfunctional states and guide the transition back to homeostasis. Pediatric tuina manipulations sufficiently, specifically, and accurately simulate certain sensory receptors in the skin, which in turn activates the internal self-healing function of the human body. We summarized the main opinions on pediatric tuina mechanism in ancient literature into three minor perspectives and demonstrated them by combining them with modern medical knowledge. First, children at a young age are more responsive to stimulations on the skin surface; second, the sensory receptors and pediatric tuina acupoints on the skin surface have a similar distribution pattern; third, the specific manipulations of pediatric tuina provide multiple stimuli that are detected by a variety of surface sensory receptors for information collection. Each point could be tested via clinical trials with appropriate-designed comparisons.
    Keywords:  acupressure; child; complementary and alternative therapy; effect theory; mechanism; traditional Chinese medicine
    DOI:  https://doi.org/10.1089/acu.2023.0105
  35. Proc Natl Acad Sci U S A. 2024 Oct;121(40): e2321182121
    miR-96-5p expression is sufficient to induce and maintain the senescent cell fate in the absence of stress.
    Fernando E Santiago, Tanvi Adige, Shamsed Mahmud, Xiao Dong, Laura J Niedernhofer, Paul D Robbins.
      Senescence is a cell fate driven by different types of stress that results in exit from the cell cycle and expression of an inflammatory senescence-associated secretory phenotype (SASP). Here, we demonstrate that stable overexpression of miR-96-5p was sufficient to induce cellular senescence in the absence of genotoxic stress, inducing expression of certain markers of early senescence including SASP factors while repressing markers of deep senescence including LINE-1 and type 1 interferons. Stable miR-96-5p overexpression led to genome-wide changes in heterochromatin followed by epigenetic activation of p16Ink4a, p21Cip1, and SASP expression, induction of a marker of DNA damage, and induction of a transcriptional signature similar to other senescent lung and endothelial cell types. Expression of miR-96-5p significantly increased following senescence induction in culture cells and with aging in tissues from naturally aged and Ercc1-/Δ progeroid mice. Mechanistically, miR-96-5p directly suppressed expression of SIN3B and SIN3 corepressor complex constituents KDM5A and MORF4L2, and siRNA-mediated knockdown of these transcriptional regulators recapitulated the senescent phenotype. In addition, pharmacologic inhibition of the SIN3 complex suppressed senescence and SASP markers. These results clearly demonstrate that a single microRNA is sufficient to drive early senescence in the absence of genotoxic stress through targeting epigenetic and transcriptional regulators, identifying novel targets for the development of senotherapeutics.
    Keywords:  SIN3B; aging; epigenetics; miRNA; senescence
    DOI:  https://doi.org/10.1073/pnas.2321182121
  36. Exp Gerontol. 2024 Sep 24. pii: S0531-5565(24)00235-3. [Epub ahead of print]197 112589
    Urolithin A prevents age-related hearing loss in C57BL/6J mice likely by inducing mitophagy.
    Sung Il Cho, Eu-Ri Jo, Hee Sun Jang.
      Mitochondrial dysfunction with aging is associated with the development of age-related hearing loss. Mitophagy is a cardinal mechanism to maintain a healthy mitochondrial population through the turnover of damaged mitochondria. Declining mitophagy with age causes a buildup of damaged mitochondria, leading to sensory organ dysfunction. The effect of Urolithin A (UA), a mitophagy inducer, was investigated on age-related hearing loss in a mouse model. C57BL/6J mice were treated with UA from 6 to 10 months of age. UA attenuated an auditory brainstem responses (ABR) threshold shift at 8, 16, and 32 kHz frequencies, and improved mitochondrial DNA integrity and ATP production in the cochlea and auditory cortex. The mRNA levels of mitophagy-related genes and protein levels of PINK1, Parkin, BNIP3, and LC3B increased in the cochlea and auditory cortex. The expression of mitophagosomes and mitophagolysosomes in the cochlea, spiral ganglion, auditory cortex, and inferior colliculus increased, together with the expression of Parkin and BNIP3 in the cochlea, spiral ganglion, auditory cortex, and inferior colliculus. These results indicate that UA counteracted mitophagy decline in the auditory system and prevented age-related hearing loss. UA can be used as a potential agent to prevent age-related hearing loss.
    Keywords:  Age-related hearing loss; Mitochondria; Mitophagy; Urolithin A
    DOI:  https://doi.org/10.1016/j.exger.2024.112589
  37. Heliyon. 2024 Sep 30. 10(18): e37545
    Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling in heavy metals-induced oxidative stress.
    Swapnil Tripathi, Gitika Kharkwal, Rajeev Mishra, Gyanendra Singh.
      Organisms encounter reactive oxidants through intrinsic metabolism and environmental exposure to toxicants. Reactive oxygen and nitrogen species (ROS, RNS) are generally considered detrimental because they induce oxidative stress. In order to combat oxidative stress, a potential modulator of cellular defense nuclear factor erythroid 2-related factor 2 (Nrf2) and its endogenous inhibitor Kelch-like ECH-associated protein 1 (Keap1) operate as a common, genetically preserved intrinsic defense system. There has been a significant increase in the amount of harmful metalloids and metals that individuals are exposed to through their food, water, and air, primarily due to human activities. Many studies have looked at the connection between the emergence of different ailments in humans and ecological exposure to metalloids, i.e., arsenic (As) and metals viz., chromium (Cr), mercury (Hg), cadmium (Cd), cobalt (Co), and lead (Pb). It is known that they can produce ROS in several organs by both direct and indirect means. Studies suggest that Nrf2 signaling is a crucial mechanism in maintaining antioxidant balance and can have two roles, depending on the particular biological setting. From one perspective, Nrf2 is an essential defense mechanism against metal-induced toxicity. Still, it may also operate as a catalyst for metal-induced carcinogenesis in situations involving protracted exposure and persistent activation. Therefore, this review aims to provide an overview of the antioxidant defense mechanism of Nrf2-Keap1 signaling and the interrelation between Nrf2 signaling and the toxic elements.
    Keywords:  Cellular defense system; Metal-induced toxicity; Nrf2-Keap1 signaling; Oxidative stress; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e37545
  38. Nat Commun. 2024 Sep 27. 15(1): 8274
    Mitochondrial protein heterogeneity stems from the stochastic nature of co-translational protein targeting in cell senescence.
    Abdul Haseeb Khan, Xuefang Gu, Rutvik J Patel, Prabha Chuphal, Matheus P Viana, Aidan I Brown, Brian M Zid, Tatsuhisa Tsuboi.
      A decline in mitochondrial function is a hallmark of aging and neurodegenerative diseases. It has been proposed that changes in mitochondrial morphology, including fragmentation of the tubular mitochondrial network, can lead to mitochondrial dysfunction, yet the mechanism of this loss of function is unclear. Most proteins contained within mitochondria are nuclear-encoded and must be properly targeted to the mitochondria. Here, we report that sustained mRNA localization and co-translational protein delivery leads to a heterogeneous protein distribution across fragmented mitochondria. We find that age-induced mitochondrial fragmentation drives a substantial increase in protein expression noise across fragments. Using a translational kinetic and molecular diffusion model, we find that protein expression noise is explained by the nature of stochastic compartmentalization and that co-translational protein delivery is the main contributor to increased heterogeneity. We observed that cells primarily reduce the variability in protein distribution by utilizing mitochondrial fission-fusion processes rather than relying on the mitophagy pathway. Furthermore, we are able to reduce the heterogeneity of the protein distribution by inhibiting co-translational protein targeting. This research lays the framework for a better understanding of the detrimental impact of mitochondrial fragmentation on the physiology of cells in aging and disease.
    DOI:  https://doi.org/10.1038/s41467-024-52183-y
  39. J Inflamm Res. 2024 ;17 6619-6633
    The Multifaceted Protective Role of Nuclear Factor Erythroid 2-Related Factor 2 in Osteoarthritis: Regulation of Oxidative Stress and Inflammation.
    Weibei Sheng, Yaohang Yue, Tiantian Qi, Haotian Qin, Peng Liu, Deli Wang, Hui Zeng, Fei Yu.
      Osteoarthritis (OA) is a chronic degenerative joint disease characterized by the degradation of joint cartilage, subchondral bone sclerosis, synovitis, and structural changes in the joint. Recent research has highlighted the role of various genes in the pathogenesis and progression of OA, with nuclear factor erythroid 2-related factor 2 (NRF2) emerging as a critical player. NRF2, a vital transcription factor, plays a key role in regulating the OA microenvironment and slowing the disease's progression. It modulates the expression of several antioxidant enzymes, such as Heme oxygenase-1 (HO-1) and NAD(P)H oxidoreductase 1 (NQO1), among others, which help reduce oxidative stress. Furthermore, NRF2 inhibits the nuclear factor kappa-B (NF-κB) signaling pathway, thereby decreasing inflammation, joint pain, and the breakdown of cartilage extracellular matrix, while also mitigating cell aging and death. This review discusses NRF2's impact on oxidative stress, inflammation, cell aging, and various cell death modes (such as apoptosis, necroptosis, and ferroptosis) in OA-affected chondrocytes. The role of NRF2 in OA macrophages, and synovial fibroblasts was also discussed. It also covers NRF2's role in preserving the cartilage extracellular matrix and alleviating joint pain. The purpose of this review is to provide a comprehensive understanding of NRF2's protective mechanisms in OA, highlighting its potential as a therapeutic target and underscoring its significance in the development of novel treatment strategies for OA.
    Keywords:  chondrocytes; inflammation; nuclear factor erythroid 2-related factor 2; osteoarthritis; oxidative stress
    DOI:  https://doi.org/10.2147/JIR.S479186
  40. Future Med Chem. 2024 Sep 24. 1-25
    Benzimidazole-based small molecules as anticancer agents targeting telomeric G-quadruplex and inhibiting telomerase enzyme.
    Hemanathan Elango, Rabindra Nath Das, Abhijit Saha.
      Telomeres, crucial for chromosomal integrity, have been related to aging and cancer formation, mainly through regulating G-quadruplex structures. G-quadruplexes are structural motifs that can arise as secondary structures of nucleic acids, especially in guanine-rich DNA and RNA regions. Targeting these structures by small compounds shows promise in the selective suppression of cell growth, opening up novel possibilities for anticancer treatment. A comprehensive investigation of the many structural forms of G-quadruplex ligands is required to create ground-breaking anticancer drugs. Recent research into using specific benzimidazole molecules in stabilizing telomeric DNA into G-quadruplex structures has highlighted their ability to influence oncogene expression and demonstrate antiproliferative characteristics against cancer cells. This review describes the benzimidazole derivative, designed to enhance the stability of the G-quadruplex structure DNA to suppress the activity of telomerase enzyme, exhibiting promising potential for anticancer therapy.
    Keywords:  Anticancer agent; DNA G-quadruplex; Ligand/small molecule interaction; Telomerase
    DOI:  https://doi.org/10.1080/17568919.2024.2400982
  41. Aging Cell. 2024 Sep 25. e14344
    Proteomic analysis across aged tissues reveals distinct signatures and the crucial involvement of midgut barrier function in the regulation of aging.
    Congying Zhang, Jinlong Wang, Tianzhao Yao, Jiaxin Hu, Feifei Sun, Chunlu Feng, Zhendong Sun, Yuzhuo Shao, Zhu Wang, Jiarui Wu, Yunpeng Huang.
      The process of aging is a natural phenomenon characterized by gradual deterioration in biological functions and systemic homeostasis, which can be modulated by both genetic and environmental factors. Numerous investigations conducted on model organisms, including nematodes, flies, and mice, have elucidated several pivotal aging pathways, such as insulin signaling and AMPK signaling. However, it remains uncertain whether the regulation of the aging process is uniform or diverse across different tissues and whether manipulating the same aging factor can result in consistent outcomes in various tissues. In this study, we utilize the Drosophila organism to investigate tissue-specific proteome signatures during the aging process. Although distinct proteins undergo changes in aged tissues, certain common altered functional networks are constituently identified across different tissues, including the decline of the mitochondrial ribosomal network, autophagic network, and anti-ROS defense networks. Furthermore, downregulation of insulin receptor (InR) in the midguts, muscle, and central nervous system (CNS) of flies leads to a significant extension in fly lifespans. Notably, despite manipulating the same aging gene InR, diverse alterations in proteins are observed across different tissues. Importantly, knockdown of InR in the midguts leads to a distinct proteome compared with other tissues, resulting in enhanced actin nucleation and glutathione metabolism, while attenuating age-related elevation of serine proteases. Consequently, knockdown of InR results in rejuvenation of the integrity of the midgut barrier and augmentation of anti-ROS defense capabilities. Our findings suggest that the barrier function of the midgut plays a pivotal role in defending against aging, underscoring the paramount importance of maintaining optimal gut physiology to effectively delay the aging process. Moreover, when considering age-related changes across various tissues, it is more reasonable to identify functional networks rather than focusing solely on individual proteins.
    Keywords:   Drosophila ; aging; gut barrier; insulin receptor; proteome
    DOI:  https://doi.org/10.1111/acel.14344
  42. Nature. 2024 Sep 26.
    Stem cells reverse woman's diabetes - a world first.
    Smriti Mallapaty.
      
    Keywords:  Cell biology; Diabetes; Stem cells
    DOI:  https://doi.org/10.1038/d41586-024-03129-3
  43. J Nutr. 2024 Sep 25. pii: S0022-3166(24)01032-0. [Epub ahead of print]
    Plant extracts and omega-3 improve short-term memory and modulate the microbiota-gut-brain axis in D-Galactose model mice.
    Marie Martin, Milan Boulaire, Céline Lucas, Adrien Peltier, Line Pourtau, David Gaudout, Sophie Layé, Véronique Pallet, Corinne Joffre, Anne-Laure Dinel.
       BACKGROUND: Aging, characterized by a slow and progressive alteration of cognitive functions, is associated with gut microbiota dysbiosis, low-grade chronic inflammation, as well as increased oxidative stress and neurofunctional alterations. Some nutrients, such as polyphenols, carotenoids, and omega-3, are good candidates to prevent age-related cognitive decline, due to their immunomodulatory, antioxidant and neuroprotective properties.
    OBJECTIVE: The objective of this study was to demonstrate the preventive effect of a combination of plant extracts (PE) containing Memophenol™ (grapes and blueberries polyphenols) and a patented saffron extract (saffron carotenoids and safranal), and omega-3 (om-3) on cognitive function in a mice model of accelerated aging and to understand the biological mechanisms involved.
    METHODS: We used an accelerated aging model by injecting 3-month-old male C57Bl6/J mice with D-galactose for 8 weeks, during which they were fed with a balanced control diet, supplemented or not with PE and/or om-3 (n=15-16/group). Short-term memory was evaluated by Y-maze test, following by analyses of hippocampal and intestinal RNA expressions, brain fatty acid and oxylipin amounts and gut microbiota composition (16S rRNA gene sequencing). Statistical analyses were performed (t-test, ANOVA and Pearson's correlation).
    RESULTS: Our results showed that oral administration of PE, om-3, or both (mix) prevented hippocampus-dependent short-term memory deficits induced by D-galactose (p<0.05). This effect was accompanied by the modulation of gut microbiota, altered by the treatment. PE and the mix increased the expression of antioxidative and neurogenesis markers, such as catalase and DCX, in hippocampus (p<0.05 for both). Moreover, om-3 and the mix showed a higher omega-3 level (p<0.05) and EPA-derived 18-HEPE (p<0.001) in prefrontal cortex. These changes may contribute to the improvement in memory.
    CONCLUSIONS: These results suggest that the mix of PE and om-3 could be more efficient at attenuating age-related cognitive decline than individual supplementations because it targeted, in mice, the different pathways impaired with aging.
    Keywords:  D-Galactose; Plant extracts; memory; microbiota; omega-3
    DOI:  https://doi.org/10.1016/j.tjnut.2024.09.015
  44. Curr Drug Targets. 2024 Sep 25.
    Targeting SERCA2 in Anti-Tumor Drug Discovery.
    Wanqian Song, Qiuju Zhang, Zhiyong Cao, Guo Jing, Tiancheng Zhan, Yongkang Yuan, Ning Kang, Qiang Zhang.
      SERCA2, a P-type ATPase located on the endoplasmic reticulum of cells, plays an important role in maintaining calcium balance within cells by transporting calcium from the cytoplasm to the endoplasmic reticulum against its concentration gradient. A multitude of studies have demonstrated that the expression of SERCA2 is abnormal in a wide variety of tumor cells. Consequently, research exploring compounds that target SERCA2 may offer a promising avenue for the development of novel anti-tumor drugs. This review has summarized the anti-tumor compounds targeting SERCA2, including thapsigargin, dihydroartemisinin, curcumin, galangin, etc. These compounds interact with SERCA2 on the endoplasmic reticulum membrane, disrupting intracellular calcium ion homeostasis, leading to tumor cell apoptosis, autophagy and cell cycle arrest, ultimately producing anti-tumor effects. Additionally, several potential research directions for compounds targeting SERCA2 as clinical anti-cancer drugs have been proposed in the review. In summary, SERCA2 is a promising anti-tumor target for drug discovery and development.
    Keywords:  Sarcoplasmic reticulum/endoplasmic reticulum calcium ATPase; autophagy; calcium ion; cell apoptosis; cell cycle arrest.; endoplasmic reticulum stress
    DOI:  https://doi.org/10.2174/0113894501325497240918042654
  45. Hum Immunol. 2024 Sep 23. pii: S0198-8859(24)00409-9. [Epub ahead of print]85(6): 111146
    Telomeres and immunodeficiencies.
    Salavoura Katerina.
      The function of the immune system is highly dependent on cellular differentiation and clonal expansion of antigen-specific lymphocytes. Telomeres are conserved DNA-protein structures of linear chromosome termini. Telomere length has been investigated to be different in various lymphocyte subpopulations depending on their function and to change with aging. Association of accelerated telomere loss compared to matched controls has already been confirmed in many syndromes with immune dysregulation. Immunodeficiencies connected with dysfunction of telomere termini are dyskeratosis congenita, ICF syndrome (Immunodeficiency, centromeric instability and facial anomalies syndrome) genetic disorders involving DNA repair and disorders involving the VDJ recombination.
    Keywords:  Immunodeficiencies; Telomeres
    DOI:  https://doi.org/10.1016/j.humimm.2024.111146
  46. Sports Med Health Sci. 2024 Dec;6(4): 358-369
    Identification of key genes and signaling pathways based on transcriptomic studies of aerobic and resistance training interventions in sarcopenia in SAMP8 mice.
    Lunyu Li, Xiaotian Guan, Ying Huang, Bo Qu, Binyu Yao, Haili Ding.
      We examined the effects of resistance and aerobic exercise on the gene expression and biometabolic processes of aging skeletal muscle in senescence-accelerated mouse/prone 8 mice, a model of sarcopenia, and compared them with senescence-accelerated mouse/resistant 1 mice acting as controls. We found that exercise improved muscle strength, endurance, fiber size, also modulated genes and pathways related to synaptic transmission, potassium transport, JAK-STAT signaling, and PI3K-Akt signaling. Our results suggested that BDNF, JAK2, RhoC, Myh6, Stat5a, Tnnc1, and other genes may mediate the beneficial effects of exercise on sarcopenia through these pathways.
    Keywords:  Aerobic training; Resistance training; Sarcopenia; Transcriptome
    DOI:  https://doi.org/10.1016/j.smhs.2024.01.005
  47. Cytokine. 2024 Sep 23. pii: S1043-4666(24)00264-3. [Epub ahead of print]184 156760
    Skin wound repairing effects of adipose mesenchymal stem cells is promoted by the combined application of insulin-like growth factor 1: The key role of miR-21-5p-mediated signaling transduction.
    Shuo Cui, Linlei Wang, Huafei Zhao, Fei Lu, Yuhua Chen, Yadong Gu.
      Mesenchymal stem cells (ADMSCs) have been applied to the treatment of skin injuries and the co-administration of cytokines can enhance the effects. In the current study, the promoting effects of insulin-like growth factor 1 (IGF-1) on the skin wound healing effects of adipose-derived MSCs (ADMSCs) were assessed and the associated mechanism was explored by focusing on miR-21-5p mediated pathways. ADMSCs were isolated from epididymis rats, and skin wounded rats were employed as the in vivo model for evaluating the effect of ADMCs on skin healing and secretion of cytokines. Then a microarray assay was employed to select potential miR target of IGF-1 on ADMSCs. The level of the selected miR was modulated in ADMSCs, and the effects on skin injuries were also assessed. Administration of ADMSCs promoted skin wound healing and induced the production of bFGF, IL-1β, PDGF, SDF-1, IGF-1, and TNF-α. The co-administration of IGF-1 and ADMSCs strengthened the effect of ADMSCs on skin wound by suppressing activity of matrix metalloproteinase-1 (MMP-1). At molecular level, the treatment of IGF-1 up-regulated miR-21-5p level in ADMSCs, which then suppressed the expression of KLF6 in injured skin tissues and promoted wound healing. The inhibition of miR-21-5p counteracted the promoting effects of IGF-1 on the skin healing effects of ADMSCs. Findings outlined in the current study indicated that IGF-1 could promote the wound healing effects of ADMSCs by up-regulating miR-21-5p level.
    Keywords:  Adipose mesenchymal stem cells; Insulin-like growth factor 1; KLF6; Matrix metalloproteinase 1; Skin wound; miR-21-5p
    DOI:  https://doi.org/10.1016/j.cyto.2024.156760
  48. Aging Cell. 2024 Sep 25. e14351
    A longevity-specific bank of induced pluripotent stem cells from centenarians and their offspring.
    Todd W Dowrey, Samuel F Cranston, Nicholas Skvir, Yvonne Lok, Brian Gould, Bradley Petrowitz, Daniel Villar, Jidong Shan, Marianne James, Mark Dodge, Anna C Belkina, Richard M Giadone, Sofiya Milman, Paola Sebastiani, Thomas T Perls, Stacy L Andersen, George J Murphy.
      Centenarians provide a unique lens through which to study longevity, healthy aging, and resiliency. Moreover, models of human aging and resilience to disease that allow for the testing of potential interventions are virtually non-existent. We obtained and characterized over 96 centenarian and offspring peripheral blood samples including those connected to functional independence data highlighting resistance to disability and cognitive impairment. Targeted methylation arrays were used in molecular aging clocks to compare and contrast differences between biological and chronological age in these specialized subjects. Isolated peripheral blood mononuclear cells (PBMCs) from 20 of these subjects were then successfully reprogrammed into high-quality induced pluripotent stem cell (iPSC) lines which were functionally characterized for pluripotency, genomic stability, and the ability to undergo directed differentiation. The result of this work is a one-of-a-kind resource for studies of human longevity and resilience that can fuel the discovery and validation of novel therapeutics for aging-related disease.
    Keywords:  centenarians; induced pluripotent stem cells; longevity
    DOI:  https://doi.org/10.1111/acel.14351
  49. Int J Biol Macromol. 2024 Sep 24. pii: S0141-8130(24)06821-1. [Epub ahead of print] 136012
    Rational design of bioengineered recombinant collagen-like protein enhances GelMA hydrogel for diabetic wound healing.
    Yimiao Li, Yan Xia, Xing Liu, Jieqi Wang, Yinan Sun, Jinxia Huang, Zhao Guo, Shuang Jia, Yufang Chen, Jie Wang, Liping Wang, Jiaqi Li, Jian Feng, Liyao Wang, Xinyu Li.
      Gelatin methacryloyl (GelMA) holds significant potential in tissue engineering; however, its clinical applications are often constrained by its lack of functional groups. To overcome this limitation, recombinant proteins with multiple biofunctional domains present a promising strategy for GelMA functionalization, enhancing its biological properties. In this study, we developed a rationally designed recombinant collagen-like protein (RC) engineered with multiple biofunctional domains, which demonstrated the ability to upregulate collagen 1α (COL-1α) expression in NIH-3 T3 cells. By utilizing EDC/NHS chemistry, the purified RC was conjugated to GelMA, resulting in GelMA-RC hydrogels that significantly improved cell viability and migration compared to unmodified GelMA. Subsequent in vivo studies showed that RC-modified GelMA exhibited superior wound healing efficacy, largely attributed to enhanced expression of cytokeratin-14 (CK-14) and COL-1α. These findings underscore the potential of RC-functionalized GelMA in promoting diabetic wound repair and suggest broader applicability for functionalizing other biomaterials.
    Keywords:  Diabetics wound repair; GelMA; Light-induced; Recombination collagen-like protein
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.136012
  50. Heliyon. 2024 Sep 30. 10(18): e37528
    ZNF521 promotes acute myeloid leukemogenesis by suppressing the expression and acetylation of SMC3.
    Rong Qin, Tongshuo Yang, Hongchao Jiang, Ming Yu.
      Zinc finger protein 521 (ZNF521) participates in the self-renewal of hematopoietic stem cells, and its abnormal expression has been implicated to promote leukemia. However, the specific role of ZNF521 in leukemia has not been fully understood. In this study, we aimed to further elucidate its role. Using acute leukemia cell line THP-1, we demonstrated that knocking down ZNF521 inhibited leukemia cell proliferation, promoted apoptosis, and induced cell arrest in G2/M phase. Interestingly, we also observed the upregulation of SMC3 expression and acetylation, as well as the downregulation of histone deacetylases 8 (HDAC8), CDK2, and CDK6. The proliferation inhibition was reversed by knocking down SMC3, suggesting the key role of SMC3 reduction in ZNF521 elevated proliferation. Conversely, ZNF521 overexpression in HL-60 cells resulted in enhanced proliferation and inhibited apoptosis. Furthermore, we discovered that ZNF521 can interact with HDAC8, which deacetylates SMC3, and the interaction promotes proliferation and suppresses apoptosis. Notably, when HDAC8 was knocked down or its activity was inhibited by a HDAC8 inhibitor, the previous observed trend was reversed. Consequently, ZNF521 plays a critical role in acute myeloid leukemogenesis by reducing the expression and acetylation of SMC3. Overall, this study sheds light on the potential for targeted treatment in highly ZNF521 expressed acute myeloid leukemia, providing a valuable clue for precise and effective therapeutic approaches.
    Keywords:  Acetylation; HDAC8; Leukemia; SMC3; ZNF521
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e37528
  51. J Funct Biomater. 2024 Sep 08. pii: 258. [Epub ahead of print]15(9):
    Advances in Zinc-Containing Bioactive Glasses: A Comprehensive Review.
    Fariborz Sharifianjazi, Mohammadjavad Sharifianjazi, Maryam Irandoost, Ketevan Tavamaishvili, Mehdi Mohabatkhah, Maziar Montazerian.
      Bioactive glasses (BGs) have attracted significant attention in the biomaterials field due to their ability to promote soft and hard tissue regeneration and their potential for various clinical applications. BGs offer enriched features through the integration of different therapeutic inorganic ions within their composition. These ions can trigger specific responses in the body conducive to a battery of applications. For example, zinc, a vital trace element, plays a role in numerous physiological processes within the human body. By incorporating zinc, BGs can inhibit bacterial growth, exert anti-inflammatory effects, and modify bioactivity, promoting better integration with surrounding tissues when used in scaffolds for tissue regeneration. This article reviews recent developments in zinc-containing BGs (ZBGs), focusing on their synthesis, physicochemical, and biological properties. ZBGs represent a significant advancement in applications extending beyond bone regeneration. Overall, their biological roles hold promise for various applications, such as bone tissue engineering, wound healing, and biomedical coatings. Ongoing research continues to explore the potential benefits of ZBGs and to optimize their properties for diverse clinical applications.
    Keywords:  bioactive glasses; biomaterials; tissue engineering; wound; zinc
    DOI:  https://doi.org/10.3390/jfb15090258
  52. FEBS Lett. 2024 Sep 27.
    Traffic light at DSB-transit regulation between gene transcription and DNA repair.
    Stefania Modafferi, Francesca Esposito, Sara Tavella, Ubaldo Gioia, Sofia Francia.
      Transcription of actively expressed genes is dampened for kilobases around DNA lesions via chromatin modifications. This is believed to favour repair and prevent genome instability. Nonetheless, mounting evidence suggests that transcription may be induced by DNA breakage, resulting in the local de novo synthesis of non-coding RNAs (ncRNAs). Such transcripts have been proposed to play important functions in both DNA damage signalling and repair. Here, we review the recently identified mechanistic details of transcriptional silencing at damaged chromatin, highlighting how post-translational histone modifications can also be modulated by the local synthesis of DNA damage-induced ncRNAs. Finally, we envision that these entangled transcriptional events at DNA breakages can be targeted to modulate DNA repair, with potential implications for locus-specific therapeutic strategies.
    Keywords:  DNA damage response; DNA double strand break; DNA repair; non‐coding RNAs; transcription
    DOI:  https://doi.org/10.1002/1873-3468.15024
  53. J Bone Miner Res. 2024 Sep 20. pii: zjae152. [Epub ahead of print]
    Deciphering the spatial distribution of Gli1-lineage cells in dental, oral, and craniofacial regions.
    Bo Li, Zhangfan Ding, Takehito Ouchi, Yueqi Liao, Bingzhi Li, Jiajing Gong, Yuhang Xie, Zhihe Zhao, Longjiang Li.
      The craniofacial bone, crucial for protecting brain tissue and supporting facial structure, undergoes continuous remodeling through mesenchymal (MSCs) or skeletal stem cells (SSCs) in their niches. Gli1 is an ideal marker for labeling MSCs and osteoprogenitors in this region, and Gli1-lineage cells are identified as pivotal for bone growth, development, repair, and regeneration. Despite its significance, the distribution of Gli1-lineage cells across the dental, oral, and craniofacial (DOC) regions remains to be systematically explored. Utilizing tissue-clearing and light sheet fluorescence microscopy (LSFM) with a Gli1CreER; tdTomatoAi14 mouse model, we mapped the spatial distribution of Gli1-lineage cells throughout the skull, focusing on calvarial bones, sutures, bone marrow, teeth, periodontium, jaw bones, and the temporomandibular joint (TMJ). We found Gli1-lineage cells widespread in these areas, underscoring their significance in DOC regions. Additionally, we observed their role in repairing calvarial bone defects, providing novel insights into craniofacial biology and stem cell niches and enhancing our understanding of stem cells and their progeny's behavior in vivo.
    Keywords:  Anatomy; Bone biology; Craniofacial biology; Light sheet fluorescence microscopy (lsfm); Lineage tracing; Stem cells; Tissue clearing
    DOI:  https://doi.org/10.1093/jbmr/zjae152
  54. Bioengineering (Basel). 2024 Sep 14. pii: 920. [Epub ahead of print]11(9):
    Comparison of Bioengineered Scaffolds for the Induction of Osteochondrogenic Differentiation of Human Adipose-Derived Stem Cells.
    Elena Fiorelli, Maria Giovanna Scioli, Sonia Terriaca, Arsalan Ul Haq, Gabriele Storti, Marta Madaghiele, Valeria Palumbo, Ermal Pashaj, Fabio De Matteis, Diego Ribuffo, Valerio Cervelli, Augusto Orlandi.
      Osteochondral lesions may be due to trauma or congenital conditions. In both cases, therapy is limited because of the difficulty of tissue repair. Tissue engineering is a promising approach that relies on designed scaffolds with variable mechanical attributes to favor cell attachment and differentiation. Human adipose-derived stem cells (hASCs) are a very promising cell source in regenerative medicine with osteochondrogenic potential. Based on the assumption that stiffness influences cell commitment, we investigated three different scaffolds: a semisynthetic animal-derived GelMA hydrogel, a combined scaffold made of rigid PEGDA coated with a thin GelMA layer and a decellularized plant-based scaffold. We investigated the role of different biomechanical stimulations in the scaffold-induced osteochondral differentiation of hASCs. We demonstrated that all scaffolds support cell viability and spontaneous osteochondral differentiation without any exogenous factors. In particular, we observed mainly osteogenic commitment in higher stiffness microenvironments, as in the plant-based one, whereas in a dense and softer matrix, such as in GelMA hydrogel or GelMA-coated-PEGDA scaffold, chondrogenesis prevailed. We can induce a specific cell commitment by combining hASCs and scaffolds with particular mechanical attributes. However, in vivo studies are needed to fully elucidate the regenerative process and to eventually suggest it as a potential approach for regenerative medicine.
    Keywords:  biomaterials; human adipose-derived stem cells; osteochondral differentiation; regenerative medicine; scaffolds; tissue engineering
    DOI:  https://doi.org/10.3390/bioengineering11090920
  55. Curr Issues Mol Biol. 2024 Sep 05. 46(9): 9895-9905
    Exercise-Induced Shear Stress Drives mRNA Translation In Vitro.
    Daniel Conde, Mario A Garcia, Manuel Gomez, Alvaro N Gurovich.
      The vascular endothelium is the first line of defense to prevent cardiovascular disease. Its optimal functioning and health are maintained by the interaction of the proteins-endothelial nitric oxide synthase (eNOS), sirtuin 1 (SIRT1), and endothelin 1 (ET1)-and the genes that encode them-NOS3, SIRT1, and EDN1, respectively. Aerobic exercise improves endothelial function by allegedly increasing endothelial shear stress (ESS). However, there are no current data exploring the acute effects of specific exercise-induced ESS intensities on these regulatory proteins and genes that are associated with endothelial function. The purpose of this study was to assess the acute changes in endothelial proteins and gene expression after exposure to low-, moderate-, and high-intensity exercise-induced ESS. Human umbilical vein endothelial cells (HUVECs) were exposed to resting ESS (18 dynes/cm2, 60 pulses per minute (PPM)), low ESS (35 dynes/cm2, 100 PPM), moderate ESS (50 dynes/cm2, 120 PPM), and high ESS (70 dynes/cm2, 150 PPM). Protein and gene expression were quantified by fluorescent Western blot and RTqPCR, respectively. All exercise conditions showed an increase in eNOS and SIRT1 expression and a decrease in NOS3 and SIRT1 gene expression when compared to resting conditions. In addition, there was no expression of ET1 and an increase in EDN1 gene expression when compared to resting conditions. These results show that (1) exercise-induced ESS increases the expressions of vascular protective proteins and (2) there is an inverse relationship between the proteins and their encoding genes immediately after exercise-induced ESS, suggesting that exercise has a previously unexplored translational role catalyzing mRNA to proteins.
    Keywords:  EDN1; ET1; NOS3; SIRT1; eNOS; endothelium; exercise-induced shear stress
    DOI:  https://doi.org/10.3390/cimb46090589
  56. Curr Osteoporos Rep. 2024 Sep 26.
    Extra-osseous Roles of the RANK-RANKL-OPG Axis with a Focus on Skeletal Muscle.
    John Gostage, Paul Kostenuik, Katarzyna Goljanek-Whysall, Ilaria Bellantuono, Eugene McCloskey, Nicolas Bonnet.
       PURPOSE OF REVIEW: This review aims to consolidate recent observations regarding extra-osseous roles of the RANK-RANKL-OPG axis, primarily within skeletal muscle.
    RECENT FINDINGS: Preclinical efforts to decipher a common signalling pathway that links the synchronous decline in bone and muscle health in ageing and disease disclosed a potential role of the RANK-RANKL-OPG axis in skeletal muscle. Evidence suggests RANKL inhibition benefits skeletal muscle function, mass, fibre-type switching, calcium homeostasis and reduces fall incidence. However, there still exists ambiguity regarding the exact mechanistic actions and subsequent functional improvements. Other potential RANK-RANKL-OPG extra-osseous roles include regulation of neural-inflammation and glucose metabolism. Growing evidence suggests the RANK-RANKL-OPG axis may play a regulatory role in extra-osseous tissues, especially in skeletal muscle. Targeting RANKL may be a novel therapy in ameliorating loss of muscle mass and function. More research is warranted to determine the causality of the RANK-RANKL-OPG axis in extra-osseous tissues, especially those affected by aging.
    Keywords:  Denosumab; Extra-osseous; NF-κB signalling; Osteoprotegerin; RANK-RANKL-OPG axis; Skeletal muscle
    DOI:  https://doi.org/10.1007/s11914-024-00890-2
  57. Front Immunol. 2024 ;15 1454142
    New insights into the role of Klotho in inflammation and fibrosis: molecular and cellular mechanisms.
    Xinyue Zhao, Donghe Han, Chun Zhao, Fengfan Yang, Zhimei Wang, Yujiao Gao, Meihua Jin, Ran Tao.
      As the body's defense mechanism against damage and infection, the inflammatory response is a pathological process that involves a range of inflammatory cells and cytokines. A healthy inflammatory response helps the body repair by eliminating dangerous irritants. However, tissue fibrosis can result from an overly intense or protracted inflammatory response. The anti-aging gene Klotho suppresses oxidation, delays aging, and fosters development of various organs. Numerous investigations conducted in the last few years have discovered that Klotho expression is changed in a variety of clinical diseases and is strongly linked to the course and outcome of a disease. Klotho functions as a co-receptor for FGF and as a humoral factor that mediates intracellular signaling pathways such as transforming growth factor β (TGF-β), toll-like receptors (TLRs), nuclear factor-kappaB (NF-κB), renin -angiotensin system (RAS), and mitogen-activated protein kinase (MAPK). It also interferes with the phenotype and function of inflammatory cells, such as monocytes, macrophages, T cells, and B cells. Additionally, it regulates the production of inflammatory factors. This article aims to examine Klotho's scientific advances in terms of tissue fibrosis and the inflammatory response in order to provide novel therapy concepts for fibrotic and inflammatory disorders.
    Keywords:  Klotho; anti-aging; inflammation; therapy; tissue fibrosis
    DOI:  https://doi.org/10.3389/fimmu.2024.1454142
  58. Biochem Pharmacol. 2024 Sep 25. pii: S0006-2952(24)00556-2. [Epub ahead of print] 116556
    Hydrogen sulfide mitigates mitochondrial dysfunction and cellular senescence in diabetic patients: Potential therapeutic applications.
    Ting Chen, Dacheng Bai, Changyong Gong, Yu Cao, Xiaoqing Yan, Renyi Peng.
      Diabetes induces a pro-aging state characterized by an increased abundance of senescent cells in various tissues, heightened chronic inflammation, reduced substance and energy metabolism, and a significant increase in intracellular reactive oxygen species (ROS) levels. This condition leads to mitochondrial dysfunction, including elevated oxidative stress, the accumulation of mitochondrial DNA (mtDNA) damage, mitophagy defects, dysregulation of mitochondrial dynamics, and abnormal energy metabolism. These dysfunctions result in intracellular calcium ion (Ca2+) homeostasis disorders, telomere shortening, immune cell damage, and exacerbated inflammation, accelerating the aging of diabetic cells or tissues. Hydrogen sulfide (H2S), a novel gaseous signaling molecule, plays a crucial role in maintaining mitochondrial function and mitigating the aging process in diabetic cells. This article systematically explores the specific mechanisms by which H2S regulates diabetes-induced mitochondrial dysfunction to delay cellular senescence, offering a promising new strategy for improving diabetes and its complications.
    Keywords:  Anti-aging; Cell senescence; Diabetes; Hydrogen sulfide; Mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.bcp.2024.116556
  59. bioRxiv. 2024 Sep 10. pii: 2024.09.09.612041. [Epub ahead of print]
    Role of the SAF-A SAP domain in X inactivation, transcription, splicing, and cell proliferation.
    Judith A Sharp, Emily Sparago, Rachael Thomas, Kaitlyn Alimenti, Wei Wang, Michael D Blower.
      SAF-A is conserved throughout vertebrates and has emerged as an important factor regulating a multitude of nuclear functions, including lncRNA localization, gene expression, and splicing. SAF-A has several functional domains, including an N-terminal SAP domain that binds directly to DNA. Phosphorylation of SAP domain serines S14 and S26 are important for SAF-A localization and function during mitosis, however whether these serines are involved in interphase functions of SAF-A is not known. In this study we tested for the role of the SAP domain, and SAP domain serines S14 and S26 in X chromosome inactivation, protein dynamics, gene expression, splicing, and cell proliferation. Here we show that the SAP domain serines S14 and S26 are required to maintain XIST RNA localization and polycomb-dependent histone modifications on the inactive X chromosome in female cells. In addition, we present evidence that an Xi localization signal resides in the SAP domain. We found that that the SAP domain is not required to maintain gene expression and plays only a minor role in mRNA splicing. In contrast, the SAF-A SAP domain, in particular serines S14 and S26, are required for normal protein dynamics, and to maintain normal cell proliferation. We propose a model whereby dynamic phosphorylation of SAF-A serines S14 and S26 mediates rapid turnover of SAF-A interactions with DNA during interphase.
    DOI:  https://doi.org/10.1101/2024.09.09.612041
  60. Curr Issues Mol Biol. 2024 Aug 23. 46(9): 9255-9268
    Dihydroavenanthramide D Enhances Skin Barrier Function through Upregulation of Epidermal Tight Junction Expression.
    Jiye Park, Jae Young Shin, Daehyun Kim, Seung-Hyun Jun, Eui Taek Jeong, Nae-Gyu Kang.
      Skin barrier dysfunction and thin epidermis are hallmarks of sensitive skin and contribute to premature aging. Avenanthramides are the primary bioactive components of colloidal oatmeal, a commonly used treatment to enhance skin barrier function. This study investigated the relationship between skin barrier function and epidermal characteristics and explored the potential of dihydroavenanthramide D (dhAvD), a synthetic avenanthramide, to improve the skin barrier. We observed a significant correlation between impaired skin barrier function and decreased epidermal thickness, suggesting that a weakened barrier contributes to increased sensitivity. Our in vitro results in HaCaT cells demonstrated that dhAvD enhances keratinocyte proliferation, migration, and tight junction protein expression, thereby strengthening the skin barrier. To mimic skin barrier dysfunction, we treated keratinocytes and full-thickness skin equivalents with IL-4 and IL-13, cytokines that are implicated in atopic dermatitis, and confirmed the downregulation of tight junction and differentiation markers. Furthermore, dhAvD treatment restored the barrier function and normalized the expression of key epidermal components, such as tight junction proteins and natural moisturizing factors, in keratinocytes treated with inflammatory cytokines. In the reconstructed human skin model, dhAvD promoted both epidermal and dermal restoration. These findings suggest that dhAvD has the potential to alleviate skin sensitivity and improve skin barrier function.
    Keywords:  anti-aging; avenanthramides; dihydroavenanthramide D; skin barrier; skin sensitivity
    DOI:  https://doi.org/10.3390/cimb46090547
  61. J Biochem. 2024 Sep 26. pii: mvae066. [Epub ahead of print]
    Correction to: The Hox-based positional memory in muscle stem cells.
      
    DOI:  https://doi.org/10.1093/jb/mvae066
  62. J Mol Cell Biol. 2024 Sep 23. pii: mjae037. [Epub ahead of print]
    Phase separation of hnRNPA1 and TERRA regulates telomeric stability.
    Ziyan Xu, Yongrui Liu, Fudong Li, Yi Yang, Hong Zhang, Xing Liu, Xin Xie, Xianjun Chen, Yunyu Shi, Liang Zhang.
      Telomeres are repetitive DNA sequences and associated protein complexes located at the end of chromatin. As a result of the DNA replication ending issue, telomeric DNA shortens during each cell cycle. The shelterin protein complex caps telomeric ends and forms a high-order protein-DNA structure to protect telomeric DNA. The stability of telomeres is critical for cellular function and is related to the progression of many human diseases. Telomeric repeat-containing RNA (TERRA) is a noncoding RNA transcribed from telomeric DNA regions. TERRA plays an essential role in regulating and maintaining the stability of telomeres. Heterogeneous nuclear ribonucleoproteins (hnRNPs) are RNA-binding proteins associated with complex and diverse biological processes. HnRNPA1 can recognize both TERRA and telomeric DNA. Previous research reported that hnRNPA1, TERRA, and POT1, a component of the shelterin complex, worked coordinately and displaced replication protein A from telomeric ssDNA after DNA replication, promoting telomere capping to preserve genomic integrity. However, the detailed molecular mechanism has remained unclear for over twenty years. Our study revealed the molecular structure through which the hnRNPA1 UP1 domain interacts with TERRA. Through structural analysis, we identified critical residues on the interacting surface between UP1 and TERRA. Furthermore, we proved that nucleic acids significantly increase the phase separation ability of hnRNPA1 and disrupting the UP1-TERRA interaction extraordinarily affects hnRNPA1 droplet formation both in vitro and in vivo. Taken together, these data revealed the molecular mechanism of the droplet formation of hnRNPA1 and TERRA and the possible function of the droplets for maintaining genomic stability.
    Keywords:  TERRA; crystal structure; hnRNPA1; phase separation; protein-RNA complex; telomeric stability
    DOI:  https://doi.org/10.1093/jmcb/mjae037
  63. Trends Pharmacol Sci. 2024 Sep 20. pii: S0165-6147(24)00166-4. [Epub ahead of print]
    Metabolic regulation in normal and leukemic stem cells.
    Cheuk-Him Man, Changzheng Li, Xi Xu, Meng Zhao.
      Hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs) are crucial for ensuring hematopoietic homeostasis and driving leukemia progression, respectively. Recent research has revealed that metabolic adaptations significantly regulate the function and survival of these stem cells. In this review, we provide an overview of how metabolic pathways regulate oxidative and proteostatic stresses in HSCs during homeostasis and aging. Furthermore, we highlight targetable metabolic pathways and explore their interactions with epigenetics and the microenvironment in addressing the chemoresistance and immune evasion capacities of LSCs. The metabolic differences between HSCs and LSCs have profound implications for therapeutic strategies.
    Keywords:  bone marrow microenvironment; drug resistance; epigenetic; hematopoietic stem cell; leukemic stem cell; metabolism; oxidative stress; proteostatic stress
    DOI:  https://doi.org/10.1016/j.tips.2024.08.004
  64. Behav Brain Res. 2024 Sep 25. pii: S0166-4328(24)00414-5. [Epub ahead of print] 115258
    Neurodegeneration: Effects of Calorie Restriction on the Brain Sirtuin Protein Levels.
    Basar Atalay, Soner Dogan, Burhan Oral Gudu, Elif Yilmaz, Atakan Ayden, Umit Ozorhan, Munevver Burcu Cicekdal, Kaan Yaltirik, Isin Dogan Ekici, Bilge Guvenc Tuna.
       BACKGROUND: Calorie restriction (CR) is suggested to activate protective mechanisms in neurodegenerative diseases (NDDs). Despite existing literature highlighting the protective role of Sirtuin (SIRT) proteins against age-related neurodegeneration (ND), no study has explored the total levels of SIRT 1, 3, and 6 proteins simultaneously in brain homogenates by ELISA following intermittent calorie restriction. Applying CR protocols in mice to induce stress, we aimed to determine whether ND would be more pronounced with ad libitum (AL) or with CR.
    METHODS: Mice were randomly assigned to ad libitum (AL), Chronic CR (CCR), or Intermittent CR (ICR) groups at 10 weeks of baseline age (BL). SIRT 1, 3, and 6 protein levels were measured in the homogenized whole-brain supernatants of 49/50 weeks old mice by the ELISA method. Neuronal morphology was evaluated by the cresyl violet on the hippocampus. Neurodegeneration (ND) was assessed by the fluoro-jade and ImageJ was used for quantifications.
    RESULTS: In the ICR group, SIRT1 levels were elevated compared to both the AL and BL groups. Similarly, the CCR group exhibited higher SIRT1 values compared to the AL and BL groups. While SIRT3 levels were higher in both the ICR and CCR groups compared to the AL and BL groups, this disparity did not reach statistical significance. SIRT6 levels were also higher in the ICR group compared to both the BL and AL groups, with the CCR group showing higher values compared to the BL and AL groups as well. Image quantification demonstrated significant neurodegeneration in the AL group compared to the CCR and ICR group, with no observed alterations in nerve cell morphology and number.
    CONCLUSION: This study revealed that the levels of SIRT 1, SIRT 3, and SIRT 6 in brain tissue were notably elevated, and there was less evidence of ND at the 50-week mark in groups undergoing continuous calorie restriction and intermittent calorie restriction compared to baseline and ad libitum groups. Our findings illustrate that CR promotes increased SIRT expression in the mouse brain, thereby potentially mitigating neurodegeneration.
    Keywords:  Calorie restriction; diet; mice brain; neurodegeneration; sirtuin
    DOI:  https://doi.org/10.1016/j.bbr.2024.115258
  65. Biochem Pharmacol. 2024 Sep 25. pii: S0006-2952(24)00554-9. [Epub ahead of print] 116554
    Exploring tryptophan metabolism: The transition from disturbed balance to diagnostic and therapeutic potential in metabolic diseases.
    Zhizhong Luo, Yuqing Liu, Xin Wang, Faxin Fan, Zhenzhen Yang, Duosheng Luo.
      The rapidly rising prevalence of metabolic diseases has turned them into an escalating global health concern. By producing or altering metabolic products, the gut microbiota plays a pivotal role in maintaining human health and influencing disease development. These metabolites originate from the host itself or the external environment. In the system of interactions between microbes and the host, tryptophan (Trp) plays a central role in metabolic processes. As the amino acid in the human body that must be obtained through dietary intake, it is crucial for various physiological functions. Trp can be metabolized in the gut into three main products: The gut microbiota regulates the transformation of 5-hydroxytryptamine (5-HT, serotonin), kynurenine (Kyn), and various indole derivatives. It has been revealed that a substantial correlation exists between alterations in Trp metabolism and the initiation and progression of metabolic disorders, including obesity, diabetes, non-alcoholic fatty liver disease, and atherosclerosis, but Trp metabolites have not been comprehensively reviewed in metabolic diseases. As such, this review summarizes and analyzes the latest research, emphasizing the importance of further studying Trp metabolism within the gut microbiota to understand and treat metabolic diseases. This carries potential significance for improving human health and may introduce new therapeutic strategies.
    Keywords:  Diagnostic; Gut microbiota; Metabolic diseases; Therapeutic potential; Tryptophan metabolism
    DOI:  https://doi.org/10.1016/j.bcp.2024.116554
  66. Cell Prolif. 2024 Sep 27. e13757
    miR-27a-3p regulates intestinal cell proliferation and differentiation through Wnt/β-catenin signalling.
    Chang Li, Yuning Zhou, Yinping Jiang, Zhijie Yin, Heidi L Weiss, Qingding Wang, B Mark Evers.
      Intestinal stem cells differentiate into absorptive enterocytes, characterised by increased brush border enzymes such as intestinal alkaline phosphatase (IAP), making up the majority (95%) of the terminally differentiated cells in the villus. Loss of integrity of the intestinal epithelium plays a key role in inflammatory diseases and gastrointestinal infection. Here, we show that the intestinal microRNA (miR)-27a-3p is an important regulator of intestinal epithelial cell proliferation and enterocyte differentiation. Repression of endogenous miR-27a-3p leads to increased enterocyte differentiation and decreased intestinal epithelial cell proliferation in mouse and human small intestinal organoids. Mechanistically, miR-27a-3p regulates intestinal cell differentiation and proliferation at least in part through the regulation of retinoic acid receptor α (RXRα), a modulator of Wnt/β-catenin signalling. Repression of miR-27a-3p increases the expression of RXRα and concomitantly, decreases the expression of active β-catenin and cyclin D1. In contrast, overexpression of miR-27a-3p mimic decreases the expression of RXRα and increases the expression of active β-catenin and cyclin D1. Moreover, overexpression of the miR-27a-3p mimic results in impaired enterocyte differentiation and increases intestinal epithelial cell proliferation. These alterations were attenuated or blocked by Wnt inhibition. Our study demonstrates an miR-27a-3p/RXRα/Wnt/β-catenin pathway that is important for the maintenance of enterocyte homeostasis in the small intestine.
    DOI:  https://doi.org/10.1111/cpr.13757
  67. Aging Dis. 2024 Aug 06.
    Early Life Interventions: Impact on Aging and Longevity.
    Rong Yuan, Aida Adlimoghaddam, Yun Zhu, Xiuqi Han, Andrzej Bartke.
      Across mammals, lifespans vary remarkably, spanning over a hundredfold difference. Comparative studies consistently reveal a strong inverse relationship between developmental pace and lifespan, hinting at the potential for early-life interventions (ELIs) to influence aging and lifespan trajectories. Focusing on postnatal interventions in mice, this review explores how ELIs influence development, lifespan, and the underlying mechanisms. Previous ELI studies have employed a diverse array of approaches, including dietary modifications, manipulations of the somatotropic axis, and various chemical treatments. Notably, these interventions have demonstrated significant impacts on aging and lifespan in mice. The underlying mechanisms likely involve pathways related to mitochondrial function, mTOR and AMPK signaling, cellular senescence, and epigenetic alterations. Interestingly, ELI studies may serve as valuable models for investigating the complex regulatory mechanisms of development and aging, particularly regarding the interplay among somatic growth, sexual maturation, and lifespan. In addition, prior research has highlighted the intricacies of experimental design and data interpretation. Factors such as timing, sex-specific effects, administration methods, and animal husbandry practices must be carefully considered to ensure the reliability and reproducibility of results, as well as rigorous interpretation. Addressing these factors is essential for advancing our understanding of how development, aging, and lifespan are regulated, potentially opening avenues for interventions that promote healthy aging.
    DOI:  https://doi.org/10.14336/AD.202.0516
  68. Biosci Rep. 2024 Sep 23. pii: BSR20240320. [Epub ahead of print]
    Asynchronous changes of hydrogen sulfide and its generating enzymes in most tissues with the aging process.
    Kaichuan He, Bo Tan, Ao Lu, Lu Bai, Chengqing Song, Yuxin Miao, Biyu Liu, Qian Chen, Xu Teng, Jing Dai, Yuming Wu.
      Aging is an inevitable and irreversible biological process that gradually heightens the risks of various diseases and death. As a newly discovered endogenous gasotransmitter, hydrogen sulfide (H2S) has been identified to exert multiple beneficial impacts on the regulation of aging and age-related pathologies. This study was aimed at systematically exploring the relationship between asynchronous aging processes and H2S concentrations in various tissues of aging mice. Samples of plasma and thirteen tissues were collected from four cross-sectional age groups (3, 6, 12 and 18 months of age) covering the lifespan of male C57BL/6J mice. The H2S concentration was quantified by a reported liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with monobromobimane (MBB) derivatization. Additionally, the expressions of CSE, CBS and 3-MST in those tissues were analyzed by western blotting. We discovered that the H2S concentrations decreased asynchronously with the aging process in plasma, heart, liver, kidney, spleen, subcutaneous fat and brown fat and increased in brain and lung. At least one of the three H2S-generating enzymes expressions was compensatorily upregulated with the aging process in most tissues, among which the up-regulation of CSE was the most prominent.
    Keywords:  3-MST; Aging; CBS; CSE; H2S
    DOI:  https://doi.org/10.1042/BSR20240320
  69. Bioinformatics. 2024 Sep 25. pii: btae577. [Epub ahead of print]
    OligoFormer: An accurate and robust prediction method for siRNA design.
    Yilan Bai, Haochen Zhong, Taiwei Wang, Zhi John Lu.
       MOTIVATION: RNA interference (RNAi) has become a widely used experimental approach for post-transcriptional regulation and is increasingly showing its potential as future targeted drugs. However, the prediction of highly efficient siRNAs (small interfering RNA) is still hindered by dataset biases, the inadequacy of prediction methods, and the presence of off-target effects. To overcome these limitations, we propose an accurate and robust prediction method, OligoFormer, for siRNA design.
    RESULTS: OligoFormer comprises three different modules including thermodynamic calculation, RNA-FM module, and Oligo encoder. Oligo encoder is the core module based on the transformer encoder. Taking siRNA and mRNA sequences as input, OligoFormer can obtain thermodynamic parameters, RNA-FM embedding, and Oligo embedding through these three modules, respectively. We carefully benchmarked OligoFormer against 6 comparable methods on siRNA efficacy datasets. OligoFormer outperforms all the other methods, with an average improvement of 9% in AUC, 6.6% in PRC, 9.8% in F1 score, and 5.1% in PCC compared to the best method among them in our inter-dataset validation. We also provide a comprehensive pipeline with prediction of siRNA efficacy and off-target effects using PITA score and TargetScan score. The ablation study shows RNA-FM module and thermodynamic parameters improved the performance and accelerated convergence of OligoFormer. The saliency maps by gradient backpropagation and base preference maps show certain base preferences in initial and terminal region of siRNAs.
    AVAILABILITY AND IMPLEMENTATION: The source code of OligoFormer is freely available on GitHub at: Https://github.com/lulab/OligoFormer. Docker image of OligoFormer is freely available on the docker hub at https://hub.docker.com/r/yilanbai/oligoformer.
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    DOI:  https://doi.org/10.1093/bioinformatics/btae577
  70. Life Sci. 2024 Sep 21. pii: S0024-3205(24)00663-5. [Epub ahead of print]357 123073
    Effect of senolytic drugs in young female mice chemically induced to estropause.
    Bianca M Ávila, Bianka M Zanini, Karina P Luduvico, Thais L Oliveira, Jéssica D Hense, Driele N Garcia, Juliane Prosczek, Francielle M Stefanello, Pedro H da Cruz, Janice L Giongo, Rodrigo A Vaucher, Jeffrey B Mason, Michal M Masternak, Augusto Schneider.
       AIMS: This study aimed to assess metabolic responses and senescent cell burden in young female mice induced to estropause and treated with senolytic drugs.
    MAIN METHODS: Estropause was induced by 4-vinylcyclohexene diepoxide (VCD) injection in two-month-old mice. The senolytics dasatinib and quercetin (D + Q) or fisetin were given by oral gavage once a month from five to 11 months of age.
    KEY FINDINGS: VCD-induced estropause led to increased body mass and reduced albumin concentrations compared to untreated cyclic mice, without affecting insulin sensitivity, lipid profile, liver enzymes, or total proteins. Estropause decreased catalase activity in adipose tissue but had no significant effect on other redox parameters in adipose and hepatic tissues. Fisetin treatment reduced ROS levels in the hepatic tissue of estropause mice. Estropause did not influence senescence-associated beta-galactosidase activity in adipose and hepatic tissues but increased senescent cell markers and fibrosis in ovaries. Senolytic treatment did not decrease ovarian cellular senescence induced by estropause.
    SIGNIFICANCE: Overall, the findings suggest that estropause leads to minor metabolic changes in young females, and the senolytics D + Q and fisetin had no protective effects despite increased ovarian senescence.
    Keywords:  D + Q; Fisetin; Menopause; Oxidative stress; Senescence; VCD
    DOI:  https://doi.org/10.1016/j.lfs.2024.123073
  71. Eur J Obstet Gynecol Reprod Biol. 2024 Sep 16. pii: S0301-2115(24)00516-5. [Epub ahead of print]302 211-215
    Investigation of Nrf2-Keap-1 pathway, Sestrin 2 and oxidative stress markers in serum of patients with placenta Accreata spectrum.
    Hafize Gökçe Gökdeniz, Neslihan Tepe Bayramoglu, Seyithan Taysi.
      Placenta accreta spectrum (PAS) is an important disease group with risks such as maternal bleeding, hysterectomy, and death, which expresses the pathological adhesion of the placenta to the uterine myometrium, including placenta accreta, increta, and percreta, with an increased incidence with an increase in cesarean section rates. In this study, we aimed to investigate the Nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-related protein 1 (Keap1) pathway in these patients. Serum Sestrin 2, Nrf2, Keap1, glycogen synthase kinase 3β (GSK-3β), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activities and malondialdehyde-modified low-density lipoprotein (MDA-LDL) levels were performed by the Enzyme-Linked Immunosorbent Assay (ELISA) method. In the findings obtained, Nrf2, Keap1, GSK-3ß, MDA-LDL levels, SOD and GSH-Px activities were statistically significantly different in the patient group compared to the control group. While MDA-LDL values were found to be high in the patient group, Nrf2, Keap1, GSK-3ß levels, SOD and GSH-Px activities were significantly lower, except for Sestrin 2 values. In addition, when grouped according to the degree of invasion, Nrf2 levels were found to be lower and Keap1 levels higher. As a result, it was determined that the Nrf2-Keap1 pathway was disrupted in PAS patients, and the oxidant/antioxidant balance was impaired in the oxidant direction. The results show that Nrf2 and Keap1 parameters can be useful in determining the degree of placental invasion.
    Keywords:  Antioxidant; Nrf2-Keap1 pathway; Oxidative stress; Placenta accreta spectrum; Sestrin 2
    DOI:  https://doi.org/10.1016/j.ejogrb.2024.09.022
  72. Mol Metab. 2024 Sep 19. pii: S2212-8778(24)00165-0. [Epub ahead of print]89 102034
    CPEB2-activated Prdm16 translation promotes brown adipocyte function and prevents obesity.
    Wen-Hsin Lu, Hui-Feng Chen, Pei-Chih King, Chi Peng, Yi-Shuian Huang.
       OBJECTIVE: Brown adipose tissue (BAT) plays an important role in mammalian thermogenesis through the expression of uncoupling protein 1 (UCP1). Our previous study identified cytoplasmic polyadenylation element binding protein 2 (CPEB2) as a key regulator that activates the translation of Ucp1 with a long 3'-untranslated region (Ucp1L) in response to adrenergic signaling. Mice lacking CPEB2 or Ucp1L exhibited reduced UCP1 expression and impaired thermogenesis; however, only CPEB2-null mice displayed obesogenic phenotypes. Hence, this study aims to investigate how CPEB2-controlled translation impacts body weight.
    METHODS: Body weight measurements were conducted on mice with global knockout (KO) of CPEB2, UCP1 or Ucp1L, as well as those with conditional knockout of CPEB2 in neurons or adipose tissues. RNA sequencing coupled with bioinformatics analysis was used to identify dysregulated gene expression in CPEB2-deficient BAT. The role of CPEB2 in regulating PRD1-BF1-RIZ1 homologous-domain containing 16 (PRDM16) expression was subsequently confirmed by RT-qPCR, Western blotting, polysomal profiling and luciferase reporter assays. Adeno-associated viruses (AAV) expressing CPEB2 or PRDM16 were delivered into BAT to assess their efficacy in mitigating weight gain in CPEB2-KO mice.
    RESULTS: We validated that defective BAT function contributed to the increased weight gain in CPEB2-KO mice. Transcriptomic profiling revealed upregulated expression of genes associated with muscle development in CPEB2-KO BAT. Given that both brown adipocytes and myocytes stem from myogenic factor 5-expressing precursors, with their cell-fate differentiation regulated by PRDM16, we identified that Prdm16 was translationally upregulated by CPEB2. Ectopic expression of PRDM16 in CPEB2-deprived BAT restored gene expression profiles and decreased weight gain in CPEB2-KO mice.
    CONCLUSIONS: In addition to Ucp1L, activation of Prdm16 translation by CPEB2 is critical for sustaining brown adipocyte function. These findings unveil a new layer of post-transcriptional regulation governed by CPEB2, fine-tuning thermogenic and metabolic activities of brown adipocytes to control body weight.
    Keywords:  Brown adipose tissue; CPEB2; Obesity; PRDM16; Thermogenesis; Translational control
    DOI:  https://doi.org/10.1016/j.molmet.2024.102034
  73. Theranostics. 2024 ;14(14): 5429-5442
    Clearance of senescent cells enhances skin wound healing in type 2 diabetic mice.
    Priyadarshani Nadeeshika Samarawickrama, Guiqin Zhang, Enfang Zhu, Xin Dong, Ayesha Nisar, Hong Zhu, Yuan Ma, Zheyan Zhou, Honglin Yang, Li Gui, Mei Cao, Wei Li, Yu Chang, Meiting Zi, Haoling Cui, Zhongping Duan, Xuan Zhang, Wen Li, Yonghan He.
      Background: Diabetic foot ulcers (DFUs) pose a substantial healthcare challenge due to their high rates of morbidity, recurrence, disability, and mortality. Current DFU therapeutics continue to grapple with multiple limitations. Senescent cells (SnCs) have been found to have a beneficial effect on acute wound healing, however, their roles in chronic wounds, such as DFU, remain unclear. Methods and results: We collected skin, fat, and muscle samples from clinical patients with DFU and lower limb fractures. RNA-sequencing combined with qPCR analyses on these samples demonstrate a significant accumulation of SnCs at DFU, as indicated by higher senescence markers (e.g., p16 and p21) and a senescence-associated secretory phenotype (SASP). We constructed a type 2 diabetic model of db/db mice, fed with a high-fat diet (Db-HFD), which were wounded using a 6 mm punch to the dorsal skin. HFD slightly affected wound healing in wild-type (WT) mice, but high glucose significantly delayed wound healing in the Db-HFD mice. We injected the mice with a previously developed fluorescent probe (XZ1208), which allows the detection of SnCs in vivo, and observed a strong senescence signal at the wound site of the Db-HFD mice. Contrary to the beneficial effects of SnCs in acute wound healing, our results demonstrated that clearance of SnCs using the senolytic compound ABT263 significantly accelerated wound healing in Db-HFD mice. Conclusion: Collectively, these findings suggest that SnCs critically accumulate at wound sites, delaying the healing process in DFUs. Thus, targeting SnCs with senolytic therapy represents a promising approach for DFU treatment, potentially improving the quality of life for patients with DFUs.
    Keywords:  cellular senescence; diabetic foot ulcer; imaging; senolytic; wound healing
    DOI:  https://doi.org/10.7150/thno.100991
  74. Biomater Adv. 2024 Sep 19. pii: S2772-9508(24)00262-0. [Epub ahead of print]166 214019
    Ionic release from bioactive SiO2-CaOCME/poly(tetrahydrofuran)/poly(caprolactone) hybrids drives human-bone marrow stromal cell osteogenic differentiation.
    David R Sory, Agathe C M Heyraud, Julian R Jones, Sara M Rankin.
      This study demonstrates that dissolution products of inorganic/organic SiO2-CaOCME/PTHF/PCL-diCOOH hybrid (70S30CCME-CL) drive human bone marrow stromal cells (h-BMSCs) down an osteogenic pathway with the production of mineralised matrix. We investigated osteogenesis through combined analyses of mRNA dynamics for key markers and targeted staining of mineralised matrix. We demonstrate that h-BMSCs undergo accelerated differentiation in vitro in response to the 70S30CCME-CL ionic milieu, as compared to incubation with osteogenic media. Extracts from 70S30CCME-CL promote osteogenesis by inducing changes in cellular metabolic activity, promoting changes in cell morphology consistent with the osteogenic lineage, and by enhancing mineralisation of hydroxyapatite in the extracellular matrix. Additionally, our results show that 70S30CCME-CL hybrids prove sustained functional resilience by maintaining osteostimulatory effects despite cumulated dissolution cycles. In co-differentiation medium, 70S30CCME-CL ionic release can modulate signalling pathways associated with non-osteogenic functions, further supporting their potential for bone regeneration applications. Overall, our study provides compelling experimental evidence that the 70S30CCME-CL hybrid is a promising biomaterial for bone tissue regeneration applications.
    Keywords:  Bioactive inorganic/organic hybrids; Bone tissue engineering; Human-bone marrow stromal cells; Osteogenic differentiation; Sol-gel
    DOI:  https://doi.org/10.1016/j.bioadv.2024.214019
  75. medRxiv. 2024 Sep 10. pii: 2024.09.06.24313206. [Epub ahead of print]
    Enhanced CRISPR/Cas-Based Immunoassay through Magnetic Proximity Extension and Detection.
    Fangchi Shao, Jiumei Hu, Pengfei Zhang, Patarajarin Akarapipad, Joon Soo Park, Hanran Lei, Kuangwen Hsieh, Tza-Huei Wang.
      Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas-associated systems have recently emerged as a focal point for developing next-generation molecular diagnosis, particularly for nucleic acid detection. However, the detection of proteins is equally critical across diverse applications in biology, medicine, and the food industry, especially for diagnosing and prognosing diseases like cancer, Alzheimer's and cardiovascular conditions. Despite recent efforts to adapt CRISPR/Cas systems for protein detection with immunoassays, these methods typically achieved sensitivity only in the femtomolar to picomolar range, underscoring the need for enhanced detection capabilities. To address this, we developed CRISPR-AMPED, an innovative CRISPR/Cas-based immunoassay enhanced by magnetic proximity extension and detection. This approach combines proximity extension assay (PEA) with magnetic beads that converts protein into DNA barcodes for quantification with effective washing steps to minimize non-specific binding and hybridization, therefore reducing background noise and increasing detection sensitivity. The resulting DNA barcodes are then detected through isothermal nucleic acid amplification testing (NAAT) using recombinase polymerase amplification (RPA) coupled with the CRISPR/Cas12a system, replacing the traditional PCR. This integration eliminates the need for thermocycling and bulky equipment, reduces amplification time, and provides simultaneous target and signal amplification, thereby significantly boosting detection sensitivity. CRISPR-AMPED achieves attomolar level sensitivity, surpassing ELISA by over three orders of magnitude and outperforming existing CRISPR/Cas-based detection systems. Additionally, our smartphone-based detection device demonstrates potential for point-of-care applications, and the digital format extends dynamic range and enhances quantitation precision. We believe CRISPR-AMPED represents a significant advancement in the field of protein detection.
    DOI:  https://doi.org/10.1101/2024.09.06.24313206
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