bims-caglex Biomed News
on Cellular aging and life extension
Issue of 2024–07–07
57 papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño
  1. Inhibitory immune checkpoints suppress the surveillance of senescent cells promoting their accumulation with aging and in age-related diseases.
  2. Insights into the epitranscriptomic role of N6-methyladenosine on aging skeletal muscle.
  3. Roles of pigment epithelium-derived factor in exercise-induced suppression of senescence and its impact on lung pathology in mice.
  4. The effects of time restricted feeding on age-related changes in the mouse retina.
  5. Developing transcriptomic signatures as a biomarker of cellular senescence.
  6. Calorie restriction and life-extending mutation downregulate miR-34a to facilitate lipid metabolism in the liver.
  7. Coffee consumption and cardiometabolic health: a comprehensive review of the evidence.
  8. Stretch-induced damage in endothelial monolayers.
  9. Targeting senescence induced by age or chemotherapy with a polyphenol-rich natural extract improves longevity and healthspan in mice.
  10. Towards a Novel Frontier in the Use of Epigenetic Clocks in Epidemiology.
  11. Long-term culture of patient-derived mammary organoids in non-biogenic electrospun scaffolds for identifying metalloprotein and motor protein activities in aging and senescence.
  12. Reversing Pdgfrβ Signaling Restores Metabolically Active Beige Adipocytes by Alleviating ILC2 Suppression in Aged and Obese Mice.
  13. Association between dietary quality and accelerated aging: a cross-sectional study of two cohorts.
  14. Sex and aging signatures of proteomics in human cerebrospinal fluid identify distinct clusters linked to neurodegeneration.
  15. A review on polyamines as promising next-generation neuroprotective and anti-aging therapy.
  16. DNA replication initiation timing is important for maintaining genome integrity.
  17. Developing AAV-delivered nonsense suppressor tRNAs for neurological disorders.
  18. Research on the anti-aging mechanisms of Panax ginseng extract in mice: a gut microbiome and metabolomics approach.
  19. Health Benefits of Intermittent Fasting.
  20. Nanofibrous Microspheres: A Biomimetic Platform for Bone Tissue Regeneration.
  21. Phytochemistry, pharmacology, toxicology and detoxification of Polygonum multiflorum Thunb.: a comprehensive review.
  22. Platelet-derived exosomes alleviate tendon stem/progenitor cell senescence and ferroptosis by regulating AMPK/Nrf2/GPX4 signaling and improve tendon-bone junction regeneration in rats.
  23. Genetic Engineering Bacillus thuringiensis Enable Melanin Biosynthesis for Anti-Tumor and Anti-Inflammation.
  24. Neuregulin 1 mitigated prolactin deficiency through enhancing TRPM8 signaling under the influence of melatonin in senescent pituitary lactotrophs.
  25. The role of BCAA metabolism in metabolic health and disease.
  26. FOXO-regulated DEAF1 controls muscle regeneration through autophagy.
  27. Comparing organic and metallo-organic hydrazone molecular cages as potential carriers for doxorubicin delivery.
  28. Accumulation of DNA G-quadruplex in mitochondrial genome hallmarks mesenchymal senescence.
  29. An updated immunosenescence exploration in healthy Chinese donors: circular elevated PD-1 on T cell and increased Ki67 on CD8+ T cell towards aging.
  30. [Exploring implementation strategies for healthy longevity among the elderly population in China based on the delphi method].
  31. IGF2BP3/NCBP1 complex inhibits renal tubular senescence through regulation of CDK6 mRNA stability.
  32. Lifespan differences in hippocampal subregion connectivity patterns during movie watching.
  33. Effect of polygenic scores of telomere length alleles on telomere length in newborns and parents.
  34. Effects of age on oxidative stress and locomotion in the pollinator, Megachile rotundata.
  35. Enhancing neuronal reticulophagy: a strategy for combating aging and APP toxicity.
  36. Alterations of receptors and insulin-like growth factor binding proteins in senescent cells.
  37. Spermidine supplementation in honey bees: Autophagy and epigenetic modifications.
  38. Extended lifespan in female Drosophila melanogaster through late-life calorie restriction.
  39. Full-length direct RNA sequencing reveals extensive remodeling of RNA expression, processing and modification in aging Caenorhabditis elegans.
  40. Multifunctional scaffolds for bone repair following age-related biological decline: Promising prospects for smart biomaterial-driven technologies.
  41. Differential effects of long- and short-term exposure to PM2.5 on accelerating telomere shortening: from in vitro to epidemiological studies.
  42. The impact of aerobic exercise timing on BMAL1 protein expression and antioxidant responses in skeletal muscle of mice.
  43. Topical application of a BCL-2 inhibitor ameliorates imiquimod-induced psoriasiform dermatitis by eliminating senescent cells.
  44. Golgi protein ACBD3 downregulation sensitizes cells to ferroptosis.
  45. Coenzyme Q10 supplementation affects cellular ionic balance: relevance to aging.
  46. Coaching ribosome biogenesis from the nuclear periphery.
  47. [Novel integrative multi-omics strategies of human's biological age computation.]
  48. Mitochondrial genetics through the lens of single-cell multi-omics.
  49. Frailty and biological age. Which best describes our aging and longevity?
  50. REV3 promotes cellular tolerance to 5-fluorodeoxyuridine by activating translesion DNA synthesis and intra-S checkpoint.
  51. Discovery of baicalein derivatives as novel inhibitors against human pancreatic lipase: Structure-activity relationships and inhibitory mechanisms.
  52. Inhibition of EZH2 Reduces Aging-Related Decline in Interstitial Cells of Cajal of the Mouse Stomach.
  53. Advances in pH Sensing: From Traditional Approaches to Next-Generation Sensors in Biological Contexts.
  54. Vimentin promotes collective cell migration through collagen networks via increased matrix remodeling and spheroid fluidity.
  55. An expedited screening platform for the discovery of anti-ageing compounds in vitro and in vivo.
  56. A Gelatin-Based Biomimetic Scaffold Promoting Osteogenic Differentiation of Adipose-Derived Mesenchymal Stem Cells.
  57. Robotising vitreoretinal surgeries.
  1. Biogerontology. 2024 Jul 01.
    Inhibitory immune checkpoints suppress the surveillance of senescent cells promoting their accumulation with aging and in age-related diseases.
    Antero Salminen.
      The accumulation of pro-inflammatory senescent cells within tissues is a common hallmark of the aging process and many age-related diseases. This modification has been called the senescence-associated secretory phenotype (SASP) and observed in cultured cells and in cells isolated from aged tissues. Currently, there is a debate whether the accumulation of senescent cells within tissues should be attributed to increased generation of senescent cells or to a defect in their elimination from aging tissues. Emerging studies have revealed that senescent cells display an increased expression of several inhibitory immune checkpoint ligands, especially those of the programmed cell death protein-1 (PD-1) ligand-1 (PD-L1) proteins. It is known that the PD-L1 ligands, especially those of cancer cells, target the PD-1 receptor of cytotoxic CD8+ T and natural killer (NK) cells disturbing their functions, e.g., evoking a decline in their cytotoxic activity and promoting their exhaustion and even apoptosis. An increase in the level of the PD-L1 protein in senescent cells was able to suppress their immune surveillance and inhibit their elimination by cytotoxic CD8+ T and NK cells. Senescent cells are known to express ligands for several inhibitory immune checkpoint receptors, i.e., PD-1, LILRB4, NKG2A, TIM-3, and SIRPα receptors. Here, I will briefly describe those pathways and examine whether these inhibitory checkpoints could be involved in the immune evasion of senescent cells with aging and age-related diseases. It seems plausible that an enhanced inhibitory checkpoint signaling can prevent the elimination of senescent cells from tissues and thus promote the aging process.
    Keywords:  Ageing; Cellular senescence; Immunosenescence; Immunosuppression; Immunosurveillance; Inflammaging
    DOI:  https://doi.org/10.1007/s10522-024-10114-w
  2. Biomed Pharmacother. 2024 Jul 03. pii: S0753-3322(24)00925-9. [Epub ahead of print]177 117041
    Insights into the epitranscriptomic role of N6-methyladenosine on aging skeletal muscle.
    Susan Enechojo Ogbe, JiDa Wang, YueXuan Shi, Ying Wang, Zhe Xu, Joseph Kofi Abankwa, Lisa Dal Pozzo, ShuWu Zhao, HuiFang Zhou, YanFei Peng, XiaoQian Chu, XiangLing Wang, YuHong Bian.
      The modification of RNA through the N6-methyladenosine (m6A) has emerged as a growing area of research due to its regulatory role in gene expression and various biological processes regulating the expression of genes. m6A RNA methylation is a post-transcriptional modification that is dynamic and reversible and found in mRNA, tRNA, rRNA, and other non-coding RNA of most eukaryotic cells. It is executed by special proteins known as "writers," which initiate methylation; "erasers," which remove methylation; and "readers," which recognize it and regulate the expression of the gene. Modification by m6A regulates gene expression by affecting the splicing, translation, stability, and localization of mRNA. Aging causes molecular and cellular damage, which forms the basis of most age-related diseases. The decline in skeletal muscle mass and functionality because of aging leads to metabolic disorders and morbidities. The inability of aged muscles to regenerate and repair after injury poses a great challenge to the geriatric populace. This review seeks to explore the m6A epigenetic regulation in the myogenesis and regeneration processes in skeletal muscle as well as the progress made on the m6A epigenetic regulation of aging skeletal muscles.
    Keywords:  aging; epigenetics; m(6)A methylation; regeneration; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1016/j.biopha.2024.117041
  3. Aging (Albany NY). 2024 Jun 26. 16
    Roles of pigment epithelium-derived factor in exercise-induced suppression of senescence and its impact on lung pathology in mice.
    Hiromichi Tsushima, Hirobumi Tada, Azusa Asai, Mikako Hirose, Tohru Hosoyama, Atsushi Watanabe, Taro Murakami, Masataka Sugimoto.
      Senescent cells contribute to tissue aging and underlie the pathology of chronic diseases. The benefits of eliminating senescent cells have been demonstrated in several disease models, and the efficacy of senolytic drugs is currently being tested in humans. Exercise training has been shown to reduce cellular senescence in several tissues; however, the mechanisms responsible remain unclear. We found that myocyte-derived factors significantly extended the replicative lifespan of fibroblasts, suggesting that myokines mediate the anti-senescence effects of exercise. A number of proteins within myocyte-derived factors were identified by mass spectrometry. Among these, pigment epithelium-derived factor (PEDF) exerted inhibitory effects on cellular senescence. Eight weeks of voluntary running increased Pedf levels in skeletal muscles and suppressed senescence markers in the lungs. The administration of PEDF reduced senescence markers in multiple tissues and attenuated the decline in respiratory function in the pulmonary emphysema mouse model. We also showed that blood levels of PEDF inversely correlated with the severity of COPD in patients. Collectively, these results strongly suggest that PEDF contributes to the beneficial effects of exercise, potentially suppressing cellular senescence and its associated pathologies.
    Keywords:  COPD; PEDF; exercise; myokine; senescence
    DOI:  https://doi.org/10.18632/aging.205976
  4. Exp Gerontol. 2024 Jul 02. pii: S0531-5565(24)00152-9. [Epub ahead of print] 112510
    The effects of time restricted feeding on age-related changes in the mouse retina.
    Cade A Huston, Madison Milan, Michaela L Vance, Marisa A Bickel, Lauren R Miller, Sharon Negri, Clara Hibbs, Hannah Vaden, Lindsay Hayes, Anna Csiszar, Zoltan Ungvari, Andriy Yabluchanskiy, Stefano Tarantini, Shannon M Conley.
      Dietary modifications such as caloric restriction (CR) and intermittent fasting (IF) have gained popularity due to their proven health benefits in aged populations. In time restricted feeding (TRF), a form of intermittent fasting, the amount of time for food intake is regulated without restricting the caloric intake. TRF is beneficial for the central nervous system to support brain health in the context of aging. Therefore, we here ask whether TRF also exerts beneficial effects in the aged retina. We compared aged mice (24 months) on a TRF paradigm (access to food for six hours per day) for either 6 or 12 months against young control mice (8 months) and aged control mice on an ad libitum diet. We examined changes in the retina at the functional (electroretinography), structural (histology and fluorescein angiograms) and molecular (gene expression) level. TRF treatment showed amelioration of age-related reductions in both scotopic and photopic b-wave amplitudes suggesting benefits for retinal interneuron signaling. TRF did not affect age-related signs of retinal inflammation or microglial activation at either the molecular or histological level. Our data indicate that TRF helps preserve some aspects of retinal function that are decreased with aging, adding to our understanding of the health benefits that altered feeding patterns may confer.
    Keywords:  Aging; Retina; Time-restricted feeding; Vascular aging
    DOI:  https://doi.org/10.1016/j.exger.2024.112510
  5. Ageing Res Rev. 2024 Jul 02. pii: S1568-1637(24)00221-6. [Epub ahead of print] 102403
    Developing transcriptomic signatures as a biomarker of cellular senescence.
    Shamsed Mahmud, Louise E Pitcher, Elijah Torbenson, Paul D Robbins, Lei Zhang, Xiao Dong.
      Cellular senescence is a cell fate driven by different types of stress, where damaged cells exit from the cell cycle and, in many cases, develop an inflammatory senescence-associated secretory phenotype (SASP). Senescence has often been linked to driving aging and the onset of multiple diseases conferred by the harmful SASP, which disrupts tissue homeostasis and impairs the regular function of many tissues. This phenomenon was first observed in vitro when fibroblasts halted replication after approximately 50 population doublings. In addition to replication-induced senescence, factors such as DNA damage and oncogene activation can induce cellular senescence both in culture and in vivo. Despite their contribution to aging and disease, identifying senescent cells in vivo has been challenging due to their heterogeneity. Although senescent cells can express the cell cycle inhibitors p16Ink4a and/or p21Cip1 and exhibit SA-ß-gal activity and evidence of a DNA damage response, there is no universal biomarker for these cells, regardless of inducer or cell type. Recent studies have analyzed the transcriptomic characteristics of these cells, leading to the identification of signature gene sets like CellAge, SeneQuest, and SenMayo. Advancements in single-cell and spatial RNA sequencing now allow for analyzing senescent cell heterogeneity within the same tissue and the development of machine learning algorithms, e.g., SenPred, SenSig, and SenCID, to discover cellular senescence using RNA sequencing data. Such insights not only deepen our understanding of the genetic pathways driving cellular senescence, but also promote the development of its quantifiable biomarkers. This review summarizes the current knowledge of transcriptomic signatures of cellular senescence and their potential as in vivo biomarkers.
    Keywords:  Cellular senescence; Machine learning; RNA sequencing
    DOI:  https://doi.org/10.1016/j.arr.2024.102403
  6. Exp Gerontol. 2024 Jun 28. pii: S0531-5565(24)00148-7. [Epub ahead of print] 112506
    Calorie restriction and life-extending mutation downregulate miR-34a to facilitate lipid metabolism in the liver.
    Sarah A Ashiqueali, Xiang Zhu, Denise Weisenborn, Adam Gesing, Augusto Schneider, Sarah A Noureddine, Christian G Correa-Garcia, Michal M Masternak, Shadab A Siddiqi.
      Ames dwarf mice (df/df) display delayed aging relative to their normal (N) siblings, living approximately 40-60 % longer. As such, investigating the mechanisms that enable these organisms to have extended lifespan is useful for the development of interventions to slow aging and deter age-related disease. Nonalcoholic fatty liver disease (NAFLD) is a condition that is characterized by the accumulation of excess adipose tissue in the liver. Previous studies highlight the potential of calorie restriction (CR) in promoting longevity, but little is known about its effects on the biomolecular processes that govern NAFLD. In this study, we examined the role of 6-month CR on genes regulating lipid metabolism in the livers of long-living df/df mice and their N littermates. Importantly, our findings showed significant downregulation of miR-34a-5p in N-CR mice and df/df mice regardless of dietary regimen. Alongside, our RT-PCR results indicated that downregulation of miR-34a-5p is correlated with the expression of metabolism-associated mRNAs involved in modulating the processes of de novo lipogenesis (DNL), fatty acid oxidation (FAO), very-low density lipoprotein transport (VLDL-T), and reverse cholesterol transport (RCT). To further verify the role of miR-34a-5p in regulating metabolic processes, we transfected the human liver cancer (HepG2) cell line with miR-34a mimic, and studied its effect on direct targets Sirt1, Ampk, and Ppara as well as downstream lipid transport regulating genes. Our findings suggest that CR and df/df life extending mutation are robust drivers of the miR-34a-5p signaling pathway and prevent the pathogenesis of age-related diseases by improving overall lipid homeostasis.
    Keywords:  Age-related diseases; Ames dwarf; Dietary intervention; mRNAs; miRNAs
    DOI:  https://doi.org/10.1016/j.exger.2024.112506
  7. Geroscience. 2024 Jul 04.
    Coffee consumption and cardiometabolic health: a comprehensive review of the evidence.
    Zoltan Ungvari, Setor K Kunutsor.
      This review provides a comprehensive synthesis of longitudinal observational and interventional studies on the cardiometabolic effects of coffee consumption. It explores biological mechanisms, and clinical and policy implications, and highlights gaps in the evidence while suggesting future research directions. It also reviews evidence on the causal relationships between coffee consumption and cardiometabolic outcomes from Mendelian randomization (MR) studies. Findings indicate that while coffee may cause short-term increases in blood pressure, it does not contribute to long-term hypertension risk. There is limited evidence indicating that coffee intake might reduce the risk of metabolic syndrome and non-alcoholic fatty liver disease. Furthermore, coffee consumption is consistently linked with reduced risks of type 2 diabetes (T2D) and chronic kidney disease (CKD), showing dose-response relationships. The relationship between coffee and cardiovascular disease is complex, showing potential stroke prevention benefits but ambiguous effects on coronary heart disease. Moderate coffee consumption, typically ranging from 1 to 5 cups per day, is linked to a reduced risk of heart failure, while its impact on atrial fibrillation remains inconclusive. Furthermore, coffee consumption is associated with a lower risk of all-cause mortality, following a U-shaped pattern, with the largest risk reduction observed at moderate consumption levels. Except for T2D and CKD, MR studies do not robustly support a causal link between coffee consumption and adverse cardiometabolic outcomes. The potential beneficial effects of coffee on cardiometabolic health are consistent across age, sex, geographical regions, and coffee subtypes and are multi-dimensional, involving antioxidative, anti-inflammatory, lipid-modulating, insulin-sensitizing, and thermogenic effects. Based on its beneficial effects on cardiometabolic health and fundamental biological processes involved in aging, moderate coffee consumption has the potential to contribute to extending the healthspan and increasing longevity. The findings underscore the need for future research to understand the underlying mechanisms and refine health recommendations regarding coffee consumption.
    Keywords:  Caffeine; Cardiometabolic; Cardiovascular disease; Chronic kidney disease; Coffee consumption; Hypertension; Mortality; Type 2 diabetes
    DOI:  https://doi.org/10.1007/s11357-024-01262-5
  8. Biomater Adv. 2024 Jun 28. pii: S2772-9508(24)00181-X. [Epub ahead of print]163 213938
    Stretch-induced damage in endothelial monolayers.
    Young Choi, Raphael Jakob, Alexander E Ehret, Lisa von Bohemer, Nikola Cesarovic, Volkmar Falk, Maximilian Y Emmert, Edoardo Mazza, Costanza Giampietro.
      Endothelial cells are constantly exposed to mechanical stimuli, of which mechanical stretch has shown various beneficial or deleterious effects depending on whether loads are within physiological or pathological levels, respectively. Vascular properties change with age, and on a cell-scale, senescence elicits changes in endothelial cell mechanical properties that together can impair its response to stretch. Here, high-rate uniaxial stretch experiments were performed to quantify and compare the stretch-induced damage of monolayers consisting of young, senescent, and aged endothelial populations. The aged and senescent phenotypes were more fragile to stretch-induced damage. Prominent damage was detected by immunofluorescence and scanning electron microscopy as intercellular and intracellular void formation. Damage increased proportionally to the applied level of deformation and, for the aged and senescent phenotype, induced significant detachment of cells at lower levels of stretch compared to the young counterpart. Based on the phenotypic difference in cell-substrate adhesion of senescent cells indicating more mature focal adhesions, a discrete network model of endothelial cells being stretched was developed. The model showed that the more affine deformation of senescent cells increased their intracellular energy, thus enhancing the tendency for cellular damage and impending detachment. Next to quantifying for the first-time critical levels of endothelial stretch, the present results indicate that young cells are more resilient to deformation and that the fragility of senescent cells may be associated with their stronger adhesion to the substrate.
    Keywords:  Aging; Cell mechanics; Endothelium; Mechanobiology; Senescence; Stretch
    DOI:  https://doi.org/10.1016/j.bioadv.2024.213938
  9. Nat Aging. 2024 Jul 01.
    Targeting senescence induced by age or chemotherapy with a polyphenol-rich natural extract improves longevity and healthspan in mice.
    Sara Zumerle, Miles Sarill, Miriam Saponaro, Manuel Colucci, Liliana Contu, Edoardo Lazzarini, Roberta Sartori, Camilla Pezzini, Anna Rinaldi, Anna Scanu, Jacopo Sgrignani, Patrizia Locatelli, Marianna Sabbadin, Aurora Valdata, Daniela Brina, Isabella Giacomini, Beatrice Rizzo, Alessandra Pierantoni, Saman Sharifi, Silvia Bressan, Claudia Altomare, Yulia Goshovska, Chiara Giraudo, Roberto Luisetto, Luca Iaccarino, Cristina Torcasio, Simone Mosole, Emiliano Pasquini, Andrea Rinaldi, Laura Pellegrini, Gregorio Peron, Matteo Fassan, Stefano Masiero, Andrea Maria Giori, Stefano Dall'Acqua, Johan Auwerx, Pietro Cippà, Andrea Cavalli, Marco Bolis, Marco Sandri, Lucio Barile, Monica Montopoli, Andrea Alimonti.
      Accumulating senescent cells within tissues contribute to the progression of aging and age-related diseases. Botanical extracts, rich in phytoconstituents, present a useful resource for discovering therapies that could target senescence and thus improve healthspan. Here, we show that daily oral administration of a standardized extract of Salvia haenkei (Haenkenium (HK)) extended lifespan and healthspan of naturally aged mice. HK treatment inhibited age-induced inflammation, fibrosis and senescence markers across several tissues, as well as increased muscle strength and fur thickness compared with age-matched controls. We also found that HK treatment reduced acutely induced senescence by the chemotherapeutic agent doxorubicin, using p16LUC reporter mice. We profiled the constituent components of HK by mass spectrometry, and identified luteolin-the most concentrated flavonoid in HK-as a senomorphic compound. Mechanistically, by performing surface plasmon resonance and in situ proximity ligation assay, we found that luteolin disrupted the p16-CDK6 interaction. This work demonstrates that administration of HK promotes longevity in mice, possibly by modulating cellular senescence and by disrupting the p16-CDK6 interaction.
    DOI:  https://doi.org/10.1038/s43587-024-00663-7
  10. Arch Med Res. 2024 Jul 01. pii: S0188-4409(24)00085-7. [Epub ahead of print]55(5): 103033
    Towards a Novel Frontier in the Use of Epigenetic Clocks in Epidemiology.
    José Jaime Martínez-Magaña, Jorge Hurtado-Soriano, Nadia Alejandra Rivero-Segura, Janitza L Montalvo-Ortiz, Paola Garcia-delaTorre, Kristhian Becerril-Rojas, Juan Carlos Gomez-Verjan.
      Health problems associated with aging are a major public health concern for the future. Aging is a complex process with wide intervariability among individuals. Therefore, there is a need for innovative public health strategies that target factors associated with aging and the development of tools to assess the effectiveness of these strategies accurately. Novel approaches to measure biological age, such as epigenetic clocks, have become relevant. These clocks use non-sequential variable information from the genome and employ mathematical algorithms to estimate biological age based on DNA methylation levels. Therefore, in the present study, we comprehensively review the current status of the epigenetic clocks and their associations across the human phenome. We emphasize the potential utility of these tools in an epidemiological context, particularly in evaluating the impact of public health interventions focused on promoting healthy aging. Our review describes associations between epigenetic clocks and multiple traits across the life and health span. Additionally, we highlighted the evolution of studies beyond mere associations to establish causal mechanisms between epigenetic age and disease. We explored the application of epigenetic clocks to measure the efficacy of interventions focusing on rejuvenation.
    Keywords:  Aging; DNA methylation; Epidemiology; Epigenetic age; Epigenetic clock
    DOI:  https://doi.org/10.1016/j.arcmed.2024.103033
  11. Adv Protein Chem Struct Biol. 2024 ;pii: S1876-1623(24)00034-8. [Epub ahead of print]141 331-360
    Long-term culture of patient-derived mammary organoids in non-biogenic electrospun scaffolds for identifying metalloprotein and motor protein activities in aging and senescence.
    Eleonora Piscitelli, Iriczalli Cruz Maya, Cinzia Cocola, Valentina Martino, Edoardo Abeni, Paride Pelucchi, Elena Angeli, Patrizia Guida, Arianna Consiglio, Giorgio Grillo, Theodoros Karnavas, Angelos Gritzapis, Mira Palizban, Ioannis Missitzis, Martin Götte, Sabino Luini, James Kehler, Cristiana Balbino, Vincenzo Guarino, Luciano Milanesi, Ileana Zucchi, Alberto Diaspro, Rolland Reinbold.
      We recently identified TMEM230 as a master regulator of the endomembrane system of cells. TMEM230 expression is necessary for promoting motor protein dependent intracellular trafficking of metalloproteins for cellular energy production in mitochondria. TMEM230 is also required for transport and secretion of metalloproteinases for autophagy and phagosome dependent clearance of misfolded proteins, defective RNAs and damaged cells, activities that decline with aging. This suggests that aberrant levels of TMEM230 may contribute to aging and regain of proper levels may have therapeutic applications. The components of the endomembrane system include the Golgi complex, other membrane bound organelles, and secreted vesicles and factors. Secreted cellular components modulate immune response and tissue regeneration in aging. Upregulation of intracellular packaging, trafficking and secretion of endosome components while necessary for tissue homeostasis and normal wound healing, also promote secretion of pro-inflammatory and pro-senescence factors. We recently determined that TMEM230 is co-regulated with trafficked cargo of the endomembrane system, including lysosome factors such as RNASET2. Normal tissue regeneration (in aging), repair (following injury) and aberrant destructive tissue remodeling (in cancer or autoimmunity) likely are regulated by TMEM230 activities of the endomembrane system, mitochondria and autophagosomes. The role of TMEM230 in aging is supported by its ability to regulate the pro-inflammatory secretome and senescence-associated secretory phenotype in tissue cells of patients with advanced age and chronic disease. Identifying secreted factors regulated by TMEM230 in young patients and patients of advanced age will facilitate identification of aging associated targets that aberrantly promote, inhibit or reverse aging. Ex situ culture of patient derived cells for identifying secreted factors in tissue regeneration and aging provides opportunities in developing therapeutic and personalized medicine strategies. Identification and validation of human secreted factors in tissue regeneration requires long-term stabile scaffold culture conditions that are different from those previously reported for cell lines used as cell models for aging. We describe a 3 dimensional (3D) platform utilizing non-biogenic and non-labile poly ε-caprolactone scaffolds that supports maintenance of long-term continuous cultures of human stem cells, in vitro generated 3D organoids and patient derived tissue. Combined with animal component free culture media, non-biogenic scaffolds are suitable for proteomic and glycobiological analyses to identify human factors in aging. Applications of electrospun nanofiber technologies in 3D cell culture allow for ex situ screening and the development of patient personalized therapeutic strategies and predicting their effectiveness in mitigating or promoting aging.
    Keywords:  3D cell culture; Aging; Animal component free tissue cultures; Autophagosomes; Autophagy; Breast; Electrospinning; Golgi complex; Hallmarks in aging; Lysosomes; Metalloproteins; Mitochondria; Motor proteins; Organoids; Polydimethylsiloxane; Proteosomes; RNASET2; Senescence; Senescent associated secreted phenotype (SASP); Skin; Stem cells (SC); TMEM230
    DOI:  https://doi.org/10.1016/bs.apcsb.2024.03.008
  12. bioRxiv. 2024 Jun 18. pii: 2024.06.17.599436. [Epub ahead of print]
    Reversing Pdgfrβ Signaling Restores Metabolically Active Beige Adipocytes by Alleviating ILC2 Suppression in Aged and Obese Mice.
    Abigail M Benvie, Daniel C Berry.
       Objective: Platelet Derived Growth Factor Receptor Beta (Pdgfrβ) suppresses the formation of cold temperature-induced beige adipocytes in aged mammals. We aimed to determine if deleting Pdgfrβ in aged mice could rejuvenate metabolically active beige adipocytes by activating group 2 innate lymphoid cells (ILC2), and whether this effect could counteract diet-induced obesity-associated beige fat decline.
    Methods: We employed Pdgfrβ gain-of-function and loss-of-function mouse models targeting beige adipocyte progenitor cells (APCs). Our approach included cold exposure, metabolic cage analysis, and age and diet-induced obesity models to examine beige fat development and metabolic function under varied Pdgfrβ activity.
    Results: Acute cold exposure alone enhanced metabolic benefits in aged mice, irrespective of beige fat generation. However, Pdgfrβ deletion in aged mice reestablished the formation of metabolically functional beige adipocytes, enhancing metabolism. Conversely, constitutive Pdgfrβ activation in young mice stymied beige fat development. Mechanistically, Pdgfrβ deletion upregulated IL-33, promoting ILC2 recruitment and activation, whereas Pdgfrβ activation reduced IL-33 levels and suppressed ILC2 activity. Notably, diet-induced obesity markedly increased Pdgfrβ expression and Stat1 signaling, which inhibited IL-33 induction and ILC2 activation. Genetic deletion of Pdgfrβ restored beige fat formation in obese mice, improving whole-body metabolism.
    Conclusion: This study reveals that cold temperature exposure alone can trigger metabolic activation in aged mammals. However, reversing Pdgfrβ signaling in aged and obese mice not only restores beige fat formation but also renews metabolic function and enhances the immunological environment of white adipose tissue (WAT). These findings highlight Pdgfrβ as a crucial target for therapeutic strategies aimed at combating age- and obesity-related metabolic decline.
    DOI:  https://doi.org/10.1101/2024.06.17.599436
  13. Food Funct. 2024 Jul 03.
    Association between dietary quality and accelerated aging: a cross-sectional study of two cohorts.
    Yue Chen, Xin Zheng, Yiming Wang, Chenan Liu, Jinyu Shi, Tong Liu, Shiqi Lin, Hailun Xie, Heyang Zhang, Xiaoyue Liu, Zhaoting Bu, Li Deng, Shouling Wu, Hanping Shi.
      Background: Diet quality significantly influences aging processes and age-related health outcomes. This study aims to explore the association between dietary quality and accelerated aging in two large cohorts. Methods: This study collected data from the Kailuan and National Health and Nutrition Examination Survey (NHANES) cohorts; participants' dietary quality was evaluated using the American Heart Association (AHA) dietary score and Healthy Eating Index-2015 (HEI-2015), respectively. Accelerated aging in participants was determined by calculating the difference between phenotypic age and chronological age. Logistic regression models were used to explore the association between dietary quality scores and accelerated aging. Additionally, variations in this association across different subgroups were investigated. To minimize the influence of excessive aging, individuals aged 75 and above were excluded in sensitivity analyses. Results: In this study, we included 33 701 participants (27.3% female, mean age 57.29 ± 11.88) from the Kailuan study and 9285 participants (50.6% female, mean age 49.83 ± 17.62) from NHANES. In the Kailuan cohort, individuals with dietary scores ranging from 3 to 5 exhibited a 22% lower risk of accelerated aging compared to those scoring between 0 and 2 (OR = 0.78, 95% CI = 0.72-0.85). Similarly, in the NHANES cohort, participants in the highest quartile of HEI-2015 experienced a 34% reduction in the risk of accelerated aging compared to those in the lowest quartile (OR = 0.66, 95% CI = 0.52-0.84). Subgroup analyses underscored a more pronounced association between dietary quality and accelerated aging among males and individuals with unhealthy lifestyles. Sensitivity analyses confirmed the robustness of the association between dietary quality and accelerated aging. Conclusion: In summary, our study found a significant association between dietary quality and accelerated aging. Better dietary quality was associated with a reduced risk of accelerated aging, particularly among males, smokers, and participants with unhealthy lifestyles.
    DOI:  https://doi.org/10.1039/d4fo02360a
  14. medRxiv. 2024 Jun 19. pii: 2024.06.18.24309102. [Epub ahead of print]
    Sex and aging signatures of proteomics in human cerebrospinal fluid identify distinct clusters linked to neurodegeneration.
    Dahun Seo, Cheolmin Matthew Lee, Catherine Apio, Gyujin Heo, Jigyasha Timsina, Pat Kohlfeld, Merce Boada, Adelina Orellana, Maria Victoria Fernandez, Agustin Ruiz, John C Morris, Suzanne E Schindler, Taesung Park, Carlos Cruchaga, Yun Ju Sung.
      Sex and age are major risk factors for chronic diseases. Recent studies examining age-related molecular changes in plasma provided insights into age-related disease biology. Cerebrospinal fluid (CSF) proteomics can provide additional insights into brain aging and neurodegeneration. By comprehensively examining 7,006 aptamers targeting 6,139 proteins in CSF obtained from 660 healthy individuals aged from 43 to 91 years old, we subsequently identified significant sex and aging effects on 5,097 aptamers in CSF. Many of these effects on CSF proteins had different magnitude or even opposite direction as those on plasma proteins, indicating distinctive CSF-specific signatures. Network analysis of these CSF proteins revealed not only modules associated with healthy aging but also modules showing sex differences. Through subsequent analyses, several modules were highlighted for their proteins implicated in specific diseases. Module 2 and 6 were enriched for many aging diseases including those in the circulatory systems, immune mechanisms, and neurodegeneration. Together, our findings fill a gap of current aging research and provide mechanistic understanding of proteomic changes in CSF during a healthy lifespan and insights for brain aging and diseases.
    DOI:  https://doi.org/10.1101/2024.06.18.24309102
  15. Eur J Pharmacol. 2024 Jun 29. pii: S0014-2999(24)00492-8. [Epub ahead of print]978 176804
    A review on polyamines as promising next-generation neuroprotective and anti-aging therapy.
    Richmond Arthur, Sumit Jamwal, Puneet Kumar.
      Neurodegenerative disorders are diseases characterized by progressive degeneration of neurons and associated structures and are a major global issue growing more widespread as the global population's average age increases. Despite several investigations on their etiology, the specific cause of these disorders remains unknown. However, there are few symptomatic therapies to treat these disorders. Polyamines (PAs) (putrescine, spermidine, and spermine) are being studied for their role in neuroprotection, aging and cognitive impairment. They are ubiquitous polycations which have relatively higher concentrations in the brain and possess pleiotropic biochemical activities, including regulation of gene expression, ion channels, mitochondria Ca2+ transport, autophagy induction, programmed cell death, and many more. Their cellular content is tightly regulated, and substantial evidence indicates that their altered levels and metabolism are strongly implicated in aging, stress, cognitive dysfunction, and neurodegenerative disorders. In addition, dietary polyamine supplementation has been reported to induce anti-aging effects, anti-oxidant effects, and improve locomotor abnormalities, and cognitive dysfunction. Thus, restoring the polyamine level is considered a promising pharmacological strategy to counteract neurodegeneration. This review highlights PAs' physiological role and the molecular mechanism underpinning their proposed neuroprotective effect in aging and neurodegenerative disorders.
    Keywords:  Autophagy; Mitochondrial dysfunction; Neurodegeneration; Neuroprotection; Oxidative stress; Polyamines
    DOI:  https://doi.org/10.1016/j.ejphar.2024.176804
  16. bioRxiv. 2024 Jun 18. pii: 2024.06.18.599555. [Epub ahead of print]
    DNA replication initiation timing is important for maintaining genome integrity.
    Tristan T Reed, Abigail H Kendal, Katherine J Wozniak, Lyle A Simmons.
      DNA replication is regulated by factors that promote or inhibit initiation. In Bacillus subtilis, YabA is a negative regulator of DNA replication initiation while the newly identified kinase CcrZ is a positive regulator. The consequences of under-initiation or over-initiation of DNA replication to genome stability remain unclear. In this work, we measure origin to terminus ratios as a proxy for replication initiation activity. We show that Δ ccrZ and several ccrZ alleles under-initiate DNA replication while ablation of yabA or overproduction of CcrZ leads to over-initiation. We find that cells under-initiating DNA replication have few incidents of replication fork stress as determined by low formation of RecA-GFP foci compared with wild type. In contrast, cells over-initiating DNA replication show levels of RecA-GFP foci formation analogous to cells directly challenged with DNA damaging agents. We show that cells under-initiating and over-initiating DNA replication were both sensitive to mitomycin C and that changes in replication initiation frequency cause increased sensitivity to genotoxic stress. With these results, we propose that cells under-initiating DNA replication are sensitive to DNA damage due to a shortage of DNA for repair through homologous recombination. For cells over-initiating DNA replication, we propose that an increase in the number of replication forks leads to replication fork stress which is further exacerbated by chromosomal DNA damage. Together, our study shows that DNA replication initiation frequency must be tightly controlled as changes in initiation influence replication fork fate and the capacity of cells to efficiently repair damage to their genetic material.
    IMPORTANCE: The regulation of DNA replication is fundamental to cell growth and cell cycle control. In eukaryotes under-initiation or over-initiation leads to genome instability. For bacteria, it is unclear how changes in replication initiation frequency impact DNA replication status and genome integrity. We show that tight regulation of DNA replication initiation is critical for maintaining genome integrity. Cells over-initiating or under-initiating DNA replication are sensitive to DNA damage. Further, cells over-initiating DNA replication experience replication fork stress at levels that phenocopy cells encountering DNA damage from the crosslinking agent mitomycin C. Our results establish the critical importance of properly regulating DNA replication initiation frequency because an imbalance in initiation results in replication fork perturbations, deficiencies in DNA repair, and genome instability.
    DOI:  https://doi.org/10.1101/2024.06.18.599555
  17. Neurotherapeutics. 2024 Jul 02. pii: S1878-7479(24)00077-1. [Epub ahead of print]21(4): e00391
    Developing AAV-delivered nonsense suppressor tRNAs for neurological disorders.
    Jiaming Wang, Guangping Gao, Dan Wang.
      Adeno-associated virus (AAV)-based gene therapy is a clinical stage therapeutic modality for neurological disorders. A common genetic defect in myriad monogenic neurological disorders is nonsense mutations that account for about 11% of all human pathogenic mutations. Stop codon readthrough by suppressor transfer RNA (sup-tRNA) has long been sought as a potential gene therapy approach to target nonsense mutations, but hindered by inefficient in vivo delivery. The rapid advances in AAV delivery technology have not only powered gene therapy development but also enabled in vivo preclinical assessment of a range of nucleic acid therapeutics, such as sup-tRNA. Compared with conventional AAV gene therapy that delivers a transgene to produce therapeutic proteins, AAV-delivered sup-tRNA has several advantages, such as small gene sizes and operating within the endogenous gene expression regulation, which are important considerations for treating some neurological disorders. This review will first examine sup-tRNA designs and delivery by AAV vectors. We will then analyze how AAV-delivered sup-tRNA can potentially address some neurological disorders that are challenging to conventional gene therapy, followed by discussing available mouse models of neurological diseases for in vivo preclinical testing. Potential challenges for AAV-delivered sup-tRNA to achieve therapeutic efficacy and safety will also be discussed.
    Keywords:  AAV; Neurological disorder; Nonsense mutation; Premature termination codon; Suppressor tRNA
    DOI:  https://doi.org/10.1016/j.neurot.2024.e00391
  18. Front Pharmacol. 2024 ;15 1415844
    Research on the anti-aging mechanisms of Panax ginseng extract in mice: a gut microbiome and metabolomics approach.
    Longfei Lin, Ruying Tang, Yuling Liu, Zhiyong Li, Hui Li, Hongjun Yang.
      Introduction: Aged-related brain damage and gut microbiome disruption are common. Research affirms that modulating the microbiota-gut-brain axis can help reduce age-related brain damage. Methods: Ginseng, esteemed in traditional Chinese medicine, is recognized for its anti-aging capabilities. However, previous Ginseng anti-aging studies have largely focused on diseased animal models. To this end, efforts were hereby made to explore the potential neuroprotective effects of fecal microbiota transplantation (FMT) from Ginseng-supplemented aged mice to those pre-treated with antibiotics. Results: As a result, FMT with specific modifications in natural aging mice improved animal weight gain, extended the telomere length, anti-oxidative stress in brain tissue, regulated the serum levels of cytokine, and balanced the proportion of Treg cells. Besides, FMT increased the abundance of beneficial bacteria of Lachnospiraceae, Dubosiella, Bacteroides, etc. and decreased the levels of potential pathogenic bacteria of Helicobacter and Lachnoclostridium in the fecal samples of natural aged mice. This revealed that FMT remarkably reshaped gut microbiome. Additionally, FMT-treated aged mice showed increased levels of metabolites of Ursolic acid, β-carotene, S-Adenosylmethionine, Spermidine, Guanosine, Celecoxib, Linoleic acid, etc., which were significantly positively correlated with critical beneficial bacteria above. Additionally, these identified critical microbiota and metabolites were mainly enriched in the pathways of Amino acid metabolism, Lipid metabolism, Nucleotide metabolism, etc. Furthermore, FMT downregulated p53/p21/Rb signaling and upregulated p16/p14, ATM/synapsin I/synaptophysin/PSD95, CREB/ERK/AKT signaling in brain damage following natural aging. Discussion: Overall, the study demonstrates that reprogramming of gut microbiota by FMT impedes brain damage in the natural aging process, possibly through the regulation of microbiota-gut-brain axis.
    Keywords:  fecal flora sequencing; fecal microbiota transplantation; ginseng; metabolomics; microbiota–gut–brain axis; natural aging
    DOI:  https://doi.org/10.3389/fphar.2024.1415844
  19. Microb Physiol. 2024 Jul 02.
    Health Benefits of Intermittent Fasting.
    B Lakshmi Reddy, Vamsee S Reddy, Milton H Saier.
      There is evidence, obtained both with animal model systems and with humans, that intermittent fasting (time restricted eating) has health benefits. These benefits include extended longevity, weight loss and counteracting various disease conditions. Such procedures influence human tissue-specific microbiomes and organellar apoptosis. In this review, we shall attempt to summarize the predominant evidence published in the scientific literature relevant to these conclusions.
    DOI:  https://doi.org/10.1159/000540068
  20. ACS Appl Bio Mater. 2024 Jul 01.
    Nanofibrous Microspheres: A Biomimetic Platform for Bone Tissue Regeneration.
    Nimeet Desai, Shreya Pande, Lalitkumar K Vora, Nagavendra Kommineni.
      Bone, a fundamental constituent of the human body, is a vital scaffold for support, protection, and locomotion, underscoring its pivotal role in maintaining skeletal integrity and overall functionality. However, factors such as trauma, disease, or aging can compromise bone structure, necessitating effective strategies for regeneration. Traditional approaches often lack biomimetic environments conducive to efficient tissue repair. Nanofibrous microspheres (NFMS) present a promising biomimetic platform for bone regeneration by mimicking the native extracellular matrix architecture. Through optimized fabrication techniques and the incorporation of active biomolecular components, NFMS can precisely replicate the nanostructure and biochemical cues essential for osteogenesis promotion. Furthermore, NFMS exhibit versatile properties, including tunable morphology, mechanical strength, and controlled release kinetics, augmenting their suitability for tailored bone tissue engineering applications. NFMS enhance cell recruitment, attachment, and proliferation, while promoting osteogenic differentiation and mineralization, thereby accelerating bone healing. This review highlights the pivotal role of NFMS in bone tissue engineering, elucidating their design principles and key attributes. By examining recent preclinical applications, we assess their current clinical status and discuss critical considerations for potential clinical translation. This review offers crucial insights for researchers at the intersection of biomaterials and tissue engineering, highlighting developments in this expanding field.
    Keywords:  Biomimetic; Bone regeneration; Microspheres; Scaffold; Tissue engineering
    DOI:  https://doi.org/10.1021/acsabm.4c00613
  21. Front Pharmacol. 2024 ;15 1427019
    Phytochemistry, pharmacology, toxicology and detoxification of Polygonum multiflorum Thunb.: a comprehensive review.
    Jiawen Qian, Chenhang Feng, Ziyang Wu, Yuanmei Yang, Xiangfu Gao, Lingyan Zhu, Yang Liu, Yuancheng Gao.
       Background: Polygonum multiflorum Thunb. (PM), a kind of perennial plant, belongs to the genus Polygonum of the family polygonaceae.The dry root of PM (also called Heshouwu), is a traditional Chinese medicine, which has a series of functions and is widely used in clinic for hair lossing, aging, and insomnia. While, PM also has some toxicity, its clinical drug safety has been concerned. In this paper, the chemical components, toxic mechanisms and detoxification strategies of PM were reviewed in order to provide evidence for its clinical application.
    Materials and methods: We conducted a systematic review of published literature of PM, including English and Chinese databases, such as PubMed, Web of Science, CNKI, and Wanfang.
    Results: PM contains a variety of chemical compounds, including stilbenes, quinones, flavonoids, phospholipids, and has many pharmacological activities such as anti-aging, wound healing, antioxidant, and anti-inflammatory properties. The PE has certain therapeutic effect, and it has certain toxicity like hepatotoxicity, nephrotoxicity, and embryotoxicity at the same time, but.these toxic effects could be effectively reduced by processing and compatibility.
    Conclusion: It is necessary to further explore the pharmacological and toxicological mechanisms of the main active compounds of PE.This article provides scientific basis for the safe clinical application of PM.
    Keywords:  Polygonum multiflorum Thunb.; chemical components; processing; toxicology; traditonal Chinese medicine
    DOI:  https://doi.org/10.3389/fphar.2024.1427019
  22. J Orthop Surg Res. 2024 Jun 28. 19(1): 382
    Platelet-derived exosomes alleviate tendon stem/progenitor cell senescence and ferroptosis by regulating AMPK/Nrf2/GPX4 signaling and improve tendon-bone junction regeneration in rats.
    Deheng Chen, Qian Tang, Wei Song, Yaohua He.
       BACKGROUND: Tendon stem/progenitor cell (TSPC) senescence contributes to tendon degeneration and impaired tendon repair, resulting in age-related tendon disorders. Ferroptosis, a unique iron-dependent form of programmed cell death, might participate in the process of senescence. However, whether ferroptosis plays a role in TSPC senescence and tendon regeneration remains unclear. Recent studies reported that Platelet-derived exosomes (PL-Exos) might provide significant advantages in musculoskeletal regeneration and inflammation regulation. The effects and mechanism of PL-Exos on TSPC senescence and tendon regeneration are worthy of further study.
    METHODS: Herein, we examined the role of ferroptosis in the pathogenesis of TSPC senescence. PL-Exos were isolated and determined by TEM, particle size analysis, western blot and mass spectrometry identification. We investigated the function and underlying mechanisms of PL-Exos in TSPC senescence and ferroptosis via western blot, real-time quantitative polymerase chain reaction, and immunofluorescence analysis in vitro. Tendon regeneration was evaluated by HE staining, Safranin-O staining, and biomechanical tests in a rotator cuff tear model in rats.
    RESULTS: We discovered that ferroptosis was involved in senescent TSPCs. Furthermore, PL-Exos mitigated the aging phenotypes and ferroptosis of TSPCs induced by t-BHP and preserved their proliferation and tenogenic capacity. The in vivo animal results indicated that PL-Exos improved tendon-bone healing properties and mechanical strength. Mechanistically, PL-Exos activated AMPK phosphorylation and the downstream nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) signaling pathway, leading to the suppression of lipid peroxidation. AMPK inhibition or GPX4 inhibition blocked the protective effect of PL-Exos against t-BHP-induced ferroptosis and senescence.
    CONCLUSION: In conclusion, ferroptosis might play a crucial role in TSPC aging. AMPK/Nrf2/GPX4 activation by PL-Exos was found to inhibit ferroptosis, consequently leading to the suppression of senescence in TSPCs. Our results provided new theoretical evidence for the potential application of PL-Exos to restrain tendon degeneration and promote tendon regeneration.
    Keywords:  AMPK/Nrf2/GPX4; Ferroptosis; Platelet-derived exosomes; Senescence
    DOI:  https://doi.org/10.1186/s13018-024-04869-8
  23. Adv Sci (Weinh). 2024 Jun 28. e2308506
    Genetic Engineering Bacillus thuringiensis Enable Melanin Biosynthesis for Anti-Tumor and Anti-Inflammation.
    Meng Chen, Bingbing Guo, Hui Cheng, Weiyi Wang, Junyi Jin, Yingyi Zhang, Xiaolian Deng, Wenjun Yang, Chenyao Wu, Xiang Gao, Dehong Yu, Wei Feng, Yu Chen.
      Collaboration between cancer treatment and inflammation management has emerged as an integral facet of comprehensive cancer care. Nevertheless, the development of interventions concurrently targeting both inflammation and cancer has encountered significant challenges stemming from various external factors. Herein, a bioactive agent synthesized by genetically engineering melanin-producing Bacillus thuringiensis (B. thuringiensis) bacteria, simultaneously achieves eco-friendly photothermal agent and efficient reactive oxygen/nitrogen species (RONS) scavenger benefits, perfectly tackling present toughies from inflammation to cancer therapies. The biologically derived melanin exhibits exceptional photothermal-conversion performance, facilitating potent photonic hyperthermia that effectively eradicates tumor cells and tissues, thereby impeding tumor growth. Additionally, the RONS-scavenging properties of melanin produced by B. thuringiensis bacteria contribute to inflammation reduction, augmenting the efficacy of photothermal tumor repression. This study presents a representative paradigm of genetic engineering in B. thuringiensis bacteria to produce functional agents tailored for diverse biomedical applications, encompassing inflammation and cancer therapy.
    Keywords:  RONS scavenger; anti‐inflammation; engineering bacteria; melanin; photothermal therapy
    DOI:  https://doi.org/10.1002/advs.202308506
  24. Int J Biol Macromol. 2024 Jul 03. pii: S0141-8130(24)04464-7. [Epub ahead of print] 133659
    Neuregulin 1 mitigated prolactin deficiency through enhancing TRPM8 signaling under the influence of melatonin in senescent pituitary lactotrophs.
    Wei Zhang, Ji-Ji Dao, Qian Li, Chong Liu, Chen-Meng Qiao, Chun Cui, Yan-Qin Shen, Wei-Jiang Zhao.
      The age-related alterations in pituitary function, including changes in prolactin (PRL) production contributes to the systemic susceptibility to age-related diseases. Our previous research has shown the involvement of Nrg1 in regulating the expression and secretion of PRL. However, the precise role of Nrg1 in mitigating the senescence of pituitary lactotrophs and the underlying mechanisms are yet to be comprehended. Here, data from the GEPIA database was used to evaluate the association between transient receptor potential cation channel subfamily M member 8 (TRPM8) and PRL in normal human pituitary tissues, followed by immunofluorescence verification using a human pituitary tissue microarray. TRPM8 levels showed a significant positive association with PRL expression in normal human pituitary tissues, and both TRPM8 and PRL levels declined during aging, suggesting that TRPM8 may regulate pituitary aging by affecting PRL production. It was also found that treatment with exogenous neuregulin 1 (Nrg1) markedly delayed the senescence of GH3 cells (rat lactotroph cell line) generated by D-galactose (D-gal). In addition, melatonin reduced the levels of senescence-related markers in senescent pituitary cells by promoting Nrg1 / ErbB4 signaling, stimulating PRL expression and secretion. Further investigation showed that Nrg1 attenuated senescence in pituitary cells by increasing TRPM8 expression. Downregulation of TRPM8 activation eliminated Nrg1-mediated amelioration of pituitary cell senescence. These findings demonstrate the critical function of Nrg1 / ErbB signaling in delaying pituitary lactotroph cell senescence and enhancing PRL production via promoting TRPM8 expression under the modulation of melatonin.
    Keywords:  Cell senescence; Melatonin; Nrg1; PRL; Pituitary lactotroph cells; TRPM8
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.133659
  25. Exp Mol Med. 2024 Jul 02.
    The role of BCAA metabolism in metabolic health and disease.
    Byeong Hun Choi, Seunghoon Hyun, Seung-Hoi Koo.
      It has long been postulated that dietary restriction is beneficial for ensuring longevity and extending the health span of mammals, including humans. In particular, a reduction in protein consumption has been shown to be specifically linked to the beneficial effect of dietary restriction on metabolic disorders, presumably by reducing the activity of the mechanistic target of rapamycin complex (mTORC) 1 and the reciprocal activation of AMP-activated protein kinase (AMPK) and sirtuin pathways. Although it is widely used as a dietary supplement to delay the aging process in humans, recent evidence suggests that branched-chain amino acids (BCAAs) might be a major cause of the deteriorating effect of a protein diet on aging and related disorders. In this review, we delineate the regulation of metabolic pathways for BCAAs at the tissue-specific level and summarize recent findings regarding the role of BCAAs in the control of metabolic health and disease in mammals.
    DOI:  https://doi.org/10.1038/s12276-024-01263-6
  26. Autophagy. 2024 Jul 04.
    FOXO-regulated DEAF1 controls muscle regeneration through autophagy.
    Kah Yong Goh, Wen Xing Lee, Sze Mun Choy, Gopal Krishnan Priyadarshini, Kenon Chua, Qian Hui Tan, Shin Yi Low, Hui San Chin, Chee Seng Wong, Shu-Yi Huang, Nai Yang Fu, Jun Nishiyama, Nathan Harmston, Hong-Wen Tang.
      The commonality between various muscle diseases is the loss of muscle mass, function, and regeneration, which severely restricts mobility and impairs the quality of life. With muscle stem cells (MuSCs) playing a key role in facilitating muscle repair, targeting regulators of muscle regeneration has been shown to be a promising therapeutic approach to repair muscles. However, the underlying molecular mechanisms driving muscle regeneration are complex and poorly understood. Here, we identified a new regulator of muscle regeneration, Deaf1 (Deformed epidermal autoregulatory factor-1) - a transcriptional factor downstream of foxo signaling. We showed that Deaf1 is transcriptionally repressed by FOXOs and that DEAF1 targets to Pik3c3 and Atg16l1 promoter regions and suppresses their expression. Deaf1 depletion therefore induces macroautophagy/autophagy, which in turn blocks MuSC survival and differentiation. In contrast, Deaf1 overexpression inactivates autophagy in MuSCs, leading to increased protein aggregation and cell death. The fact that Deaf1 depletion and its overexpression both lead to defects in muscle regeneration highlights the importance of fine tuning DEAF1-regulated autophagy during muscle regeneration. We further showed that Deaf1 expression is altered in aging and cachectic MuSCs. Manipulation of Deaf1 expression can attenuate muscle atrophy and restore muscle regeneration in aged mice or mice with cachectic cancers. Together, our findings unveil an evolutionarily conserved role for DEAF1 in muscle regeneration, providing insights into the development of new therapeutic strategies against muscle atrophy.
    Keywords:  Autophagy; Deaf1; FOXO; cancer cachexia; muscle; sarcopenia
    DOI:  https://doi.org/10.1080/15548627.2024.2374693
  27. Chem Sci. 2024 Jul 03. 15(26): 10010-10017
    Comparing organic and metallo-organic hydrazone molecular cages as potential carriers for doxorubicin delivery.
    Giovanni Montà-González, David Bastante-Rodríguez, Alba García-Fernández, Paul J Lusby, Ramón Martínez-Máñez, Vicente Martí-Centelles.
      Molecular cages are three-dimensional supramolecular structures that completely wrap guest molecules by encapsulation. We describe a rare comparative study between a metallo-organic cage and a fully organic analogous system, obtained by hydrazone bond formation self-assembly. Both cages are able to encapsulate the anticancer drug doxorubicin, with the organic cage forming a 1 : 1 inclusion complex with μM affinity, whereas the metallo-organic host experiences disassembly by interaction with the drug. Stability experiments reveal that the ligands of the metallo-organic cage are displaced in buffer at neutral, acidic, and basic pH, while the organic cage only disassembles under acidic conditions. Notably, the organic cage also shows minimal cell toxicity, even at high doses, whilst the doxorubicin-cage complex shows in vitro anti-cancer activity. Collectively, these results show that the attributes of the pure organic molecular cage are suitable for the future challenges of in vivo drug delivery using molecular cages.
    DOI:  https://doi.org/10.1039/d4sc02294g
  28. Aging Cell. 2024 Jul 02. e14265
    Accumulation of DNA G-quadruplex in mitochondrial genome hallmarks mesenchymal senescence.
    Kangkang Yu, Feifei Li, Ling Ye, Fanyuan Yu.
      Searching for biomarkers of senescence remains necessary and challenging. Reliable and detectable biomarkers can indicate the senescence condition of individuals, the need for intervention in a population, and the effectiveness of that intervention in controlling or delaying senescence progression and senescence-associated diseases. Therefore, it is of great importance to fulfill the unmet requisites of senescence biomarkers especially when faced with the growing global senescence nowadays. Here, we established that DNA G-quadruplex (G4) in mitochondrial genome was a reliable hallmark for mesenchymal senescence. Via developing a versatile and efficient mitochondrial G4 (mtG4) probe we revealed that in multiple types of senescence, including chronologically healthy senescence, progeria, and replicative senescence, mtG4 hallmarked aged mesenchymal stem cells. Furthermore, we revealed the underlying mechanisms by which accumulated mtG4, specifically within respiratory chain complex (RCC) I and IV loci, repressed mitochondrial genome transcription, finally impairing mitochondrial respiration and causing mitochondrial dysfunction. Our findings endowed researchers with the visible senescence biomarker based on mitochondrial genome and furthermore revealed the role of mtG4 in inhibiting RCC genes transcription to induce senescence-associated mitochondrial dysfunction. These findings depicted the crucial roles of mtG4 in predicting and controlling mesenchymal senescence.
    Keywords:  G‐quadruplex; biomarker; mesenchymal stem cell; mitochondrial genome; senescence
    DOI:  https://doi.org/10.1111/acel.14265
  29. Aging (Albany NY). 2024 Jun 29. 16
    An updated immunosenescence exploration in healthy Chinese donors: circular elevated PD-1 on T cell and increased Ki67 on CD8+ T cell towards aging.
    Yue Chang, Wei Cao, Lianfeng Lu, Yang Han, Lin Qin, Baotong Zhou, Taisheng Li.
      Immunosenescence is a process of immune dysfunction that occurs along with aging. Many studies have focused on the changes of different lymphocyte subsets in diseases and immune aging. However, the fluctuation in the number and phenotype of lymphocyte subset caused by aging have not been comprehensively analyzed, especially the effects of new indicators such as PD-1 and Ki67 in peripheral blood have been rarely reported. We further investigated the humoral and cellular immune parameters of 150 healthy donors over 18 years old. Age was associated with decreased CD4+CD45RA+CD62L+ T cells, decreased CD4+CD45RA+CD31+ T cells, and increased memory CD4+ or CD8+ T cells, dominated by male CD8+ T cells. The loss of CD28 expression on T cells and the transverse trend of activated CD38 and HLA-DR were also related to the increased age. In addition, CD8+ T cells in men were more prominent in activation indicators, and the difference between the old and young groups was obvious. CD4+CD25+CD127- T cells percentage tended to decrease with age and did not differ significantly between gender. Interestingly, we found that age was positively associated with PD-1+ T cells and showed significant age-related variability in men. Similarly, the percentage of CD8+ki-67+ also showed an increasing trend, with significant differences between the young group and other elderly groups in males. Our findings can provide immunological clues for future aging research, offering new insights for clinical monitoring and prevention of certain diseases.
    Keywords:  aging; flow cytometry; immunophenotyping; immunosenescence; lymphocyte subsets
    DOI:  https://doi.org/10.18632/aging.205985
  30. Zhonghua Yu Fang Yi Xue Za Zhi. 2024 Jun 06. 58(6): 883-890
    [Exploring implementation strategies for healthy longevity among the elderly population in China based on the delphi method].
    X Chai, J Cui, L L Ye, Y B Lyu, R T Shao, J Zhang, X M Shi.
      Objective: To explore the implementation strategies for promoting healthy longevity among the elderly population in China based on the Delphi method. Methods: Through literature review and expert discussion, a framework for implementation strategies to achieve healthy longevity among the elderly was determined, and a preliminary checklist of implementation strategies was developed. The Delphi method was employed from August to December 2022, inviting 25 experts from various disciplines such as clinical medicine, public health, basic research, and the elderly care services industry. Experts were sent consultation questionnaires via email to assess the importance, feasibility, judgment basis and familiarity of each implementation strategy. Active coefficient, authority coefficient, and harmony coefficient were analyzed to ultimately determine the important and feasible implementation strategies for healthy longevity that were suitable for the Chinese elderly population. Results: The expert active coefficients of the two rounds were 96.00% (24/25) and 79.17% (19/24). The authority coefficients were (0.76±0.19) and (0.77±0.17). The average scores of importance were (4.32±0.84) and (4.36±0.82), and the corresponding scores of feasibility were (3.72±1.04) and (3.80±0.92). The harmony coefficients for the importance score were 0.269 (χ2=594.084, P<0.001) and 0.159 (χ2=193.624, P<0.001). The harmony coefficients for feasibility scores were 0.205 (χ2=452.008, P<0.001) and 0.167 (χ2=202.878, P<0.001). The final eight implementation strategies were identified after two rounds of consultation. Conclusion: Through two rounds of Delphi consultations, eight important and feasible implementation strategies for promoting healthy longevity that are suitable for the Chinese context have been proposed.
    DOI:  https://doi.org/10.3760/cma.j.cn112150-20230804-00056
  31. Transl Res. 2024 Jun 28. pii: S1931-5244(24)00139-7. [Epub ahead of print]273 1-15
    IGF2BP3/NCBP1 complex inhibits renal tubular senescence through regulation of CDK6 mRNA stability.
    Yaqin Li, Congwei Luo, Yating Cai, Yan Wu, Tao Shu, Jingyan Wei, Hongsheng Wang, Hongxin Niu.
      Renal aging and the subsequent rise in kidney-related diseases are attributed to senescence in renal tubular epithelial cells (RTECs). Our study revealed that the abnormal expression of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), a reader of RNA N6-methyladenosine, is critically involved in cisplatin-induced renal tubular senescence. In cisplatin-induced senescence of RTECs, the promoter activity and transcription of IGF2BP3 is markedly suppressed. It was due to the down regulation of MYC proto-oncogene (MYC), which regulates IGF2BP3 transcription by binding to the putative site at 1852-1863 of the IGF2BP3 promoter. Overexpression of IGF2BP3 ameliorated cisplatin-induced renal tubular senescence in vitro. Mechanistic studies revealed that IGF2BP3 inhibits cellular senescence in RTECs by enhancing cyclin-dependent kinase 6 (CDK6) mRNA stability and increasing its expression. The inhibition effect of IGF2BP3 on tubular senescence is partially reversed by the knockdown of CDK6. Further, IGF2BP3 recruits nuclear cap binding protein subunit 1 (NCBP1) and inhibits CDK6 mRNA decay, by recognizing m6A modification. Specifically, IGF2BP3 recognizes m6A motif "GGACU" at nucleotides 110-114 in the 5' untranslated region (UTR) field of CDK6 mRNA. The involvement of IGF2BP3/CDK6 in alleviating tubular senescence was confirmed in a cisplatin-induced acute kidney injury (AKI)-to-chronic kidney disease (CKD) model. Clinical data also suggests an age-related decrease in IGF2BP3 and CDK6 levels in renal tissue or serum samples from patients. These findings suggest that IGF2BP3/CDK6 may be a promising target in cisplatin-induced tubular senescence and renal failure.
    Keywords:  CDK6; Cellular senescence; IGF2BP3; mRNA stability
    DOI:  https://doi.org/10.1016/j.trsl.2024.06.004
  32. Neurobiol Aging. 2024 Jun 30. pii: S0197-4580(24)00124-6. [Epub ahead of print]141 182-193
    Lifespan differences in hippocampal subregion connectivity patterns during movie watching.
    Cam CAN
      Age-related episodic memory decline is attributed to functional alternations in the hippocampus. Less clear is how aging affects the functional connections of the hippocampus to the rest of the brain during episodic memory processing. We examined fMRI data from the CamCAN dataset, in which a large cohort of participants watched a movie (N = 643; 18-88 years), a proxy for naturalistic episodic memory encoding. We examined connectivity profiles across the lifespan both within the hippocampus (anterior, posterior), and between the hippocampal subregions and cortical networks. Aging was associated with reductions in contralateral (left, right) but not ipsilateral (anterior, posterior) hippocampal subregion connectivity. Aging was primarily associated with increased coupling between the anterior hippocampus and regions affiliated with Control, Dorsal Attention and Default Mode networks, yet decreased coupling between the posterior hippocampus and a selection of these regions. Differences in age-related hippocampal-cortical, but not within-hippocampus circuitry selectively predicted worse memory performance. Our findings comprehensively characterize hippocampal functional topography in relation to cognition in older age, suggesting that shifts in cortico-hippocampal connectivity may be sensitive markers of age-related episodic memory decline.
    Keywords:  Aging; Episodic memory; Functional connectivity; Hippocampus
    DOI:  https://doi.org/10.1016/j.neurobiolaging.2024.06.006
  33. Aging Cell. 2024 Jun 28. e14241
    Effect of polygenic scores of telomere length alleles on telomere length in newborns and parents.
    Yunsung Lee, Astanand Jugessur, Håkon K Gjessing, Jennifer R Harris, Ezra Susser, Per Magnus, Abraham Aviv.
      In adults, polygenic scores (PGSs) of telomere length (TL) alleles explain about 4.5% of the variance in TL, as measured by quantitative polymerase chain reaction (qPCR). Yet, these PGSs strongly infer a causal role of telomeres in aging-related diseases. To better understand the determinants of TL through the lifespan, it is essential to examine to what extent these PGSs explain TL in newborns. This study investigates the effect of PGSs on TL in both newborns and their parents, with TL measured by Southern blotting and expressed in base-pairs (bp). Additionally, the study explores the impact of PGSs related to transmitted or non-transmitted alleles on TL in newborns. For parents and newborns, the PGS effects on TL were 172 bp (p =  2.03 × 10-15) and 161 bp (p =  3.06 × 10-8), explaining 6.6% and 5.2% of the TL variance, respectively. The strongest PGS effect was shown for maternally transmitted alleles in newborn girls, amounting to 214 bp (p =  3.77 × 10-6) and explaining 7.8% of the TL variance. The PGS effect of non-transmitted alleles was 56 bp (p = 0.0593) and explained 0.6% of the TL variance. Our findings highlight the importance of TL genetics in understanding early-life determinants of TL. They point to the potential utility of PGSs composed of TL alleles in identifying susceptibility to aging-related diseases from birth and reveal the presence of sexual dimorphism in the effect of TL alleles on TL in newborns. Finally, we attribute the higher TL variance explained by PGSs in our study to TL measurement by Southern blotting.
    Keywords:  Norwegian Mother, Father and Child Cohort Study; Southern blot; genetic nurturing; leukocyte telomere length; newborn; polygenic score; sex; triad design
    DOI:  https://doi.org/10.1111/acel.14241
  34. J Insect Physiol. 2024 Jul 03. pii: S0022-1910(24)00054-4. [Epub ahead of print] 104666
    Effects of age on oxidative stress and locomotion in the pollinator, Megachile rotundata.
    Jacob Benjamin Pithan, Joseph Rinehart, Kendra Greenlee, Giancarlo López-Martínez.
      Despite numerous aging studies, the relationship between oxidative stress, aging, and decline in functions such as locomotion is still debated. Insects offer a promising model for analyzing the relationship between oxidative stress and aging, because they exhibit vast differences in lifespan that may be affected by the environment, social factors, levels of activity, and aging interventions. In this study, we explore the effects of aging on oxidative stress and locomotion using the pollinator, Megachile rotundata, a species that is very mobile and active in the adult stage. Across the adult lifespan of M. rotundata, we assessed changes in walking, flight, oxidative damage, and antioxidant defenses. Our results suggest that M. rotundata experience age-related declines in flight, but not walking. Additionally, we found that oxidative damage and antioxidant capacity initially increase with age and physical activity, but then levels are maintained. Overall, these data show that M. rotundata, like some other organisms, may not perfectly follow the free radical theory of aging.
    Keywords:  Aging; Locomotion; Oxidative stress; Pollinator
    DOI:  https://doi.org/10.1016/j.jinsphys.2024.104666
  35. Autophagy. 2024 Jul 04.
    Enhancing neuronal reticulophagy: a strategy for combating aging and APP toxicity.
    Wenqing Mou, Yixian Cui.
      Reticulophagy, which directs the endoplasmic reticulum (ER) to the phagophore for sequestration within an autophagosome and subsequent lysosomal degradation via specific receptors, is essential for ER quality control and is implicated in various diseases. This study utilizes Drosophila to establish an in vivo model for reticulophagy. Starvation-induced reticulophagy is detected across multiple tissues in Drosophila. Whole-body upregulation or downregulation of the expression of reticulophagy receptors, atl and Rtnl1, negatively affects fly health. Notably, moderate upregulation of reticulophagy in neuronal tissues by overexpressing these receptors reduces age-related degeneration. In a Drosophila Alzheimer model expressing human APP (amyloid beta precursor protein), reticulophagy is compromised. Correcting reticulophagy by enhancing atl and Rtnl1 expression in the neurons promotes APP degradation, significantly reducing neurodegenerative symptoms. However, overexpression of mutated atl and Rtnl1, which disrupts the interaction of the corresponding proteins with Atg8, does not alleviate these symptoms, emphasizing the importance of receptor functionality. These findings support modulating reticulophagy as a therapeutic strategy for aging and neurodegenerative diseases associated with ER protein accumulation.
    Keywords:  Aging; Rtnl1; amyloid beta precursor protein; atl; receptor; reticulophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2375086
  36. Eur J Cell Biol. 2024 Jun 28. pii: S0171-9335(24)00055-4. [Epub ahead of print]103(3): 151438
    Alterations of receptors and insulin-like growth factor binding proteins in senescent cells.
    Julia Matuszewska, Adrianna Krawiec, Artur Radziemski, Paweł Uruski, Andrzej Tykarski, Justyna Mikuła-Pietrasik, Krzysztof Książek.
      The knowledge about cellular senescence expands dynamically, providing more and more conclusive evidence of its triggers, mechanisms, and consequences. Senescence-associated secretory phenotype (SASP), one of the most important functional traits of senescent cells, is responsible for a large extent of their context-dependent activity. Both SASP's components and signaling pathways are well-defined. A literature review shows, however, that a relatively underinvestigated aspect of senescent cell autocrine and paracrine activity is the change in the production of proteins responsible for the reception and transmission of SASP signals, i.e., receptors and binding proteins. For this reason, we present in this article the current state of knowledge regarding senescence-associated changes in cellular receptors and insulin-like growth factor binding proteins. We also discuss the role of these alterations in senescence induction and maintenance, pro-cancerogenic effects of senescent cells, and aging-related structural and functional malfunctions.
    Keywords:  Aging; Cellular senescence; Cytokine receptors; Insulin-like growth factor binding proteins; SASP
    DOI:  https://doi.org/10.1016/j.ejcb.2024.151438
  37. PLoS One. 2024 ;19(7): e0306430
    Spermidine supplementation in honey bees: Autophagy and epigenetic modifications.
    Danijela Kojić, Jelena Spremo, Srđana Đorđievski, Tatjana Čelić, Elvira Vukašinović, Ivan Pihler, Jelena Purać.
      Polyamines (PAs), including putrescine (Put), spermidine (Spd), and spermine (Spm), are essential polycations with wide-ranging roles in cellular functions. PA levels decline with age, making exogenous PA supplementation, particularly Spd, an intriguing prospect. Previous research in honey bees demonstrated that millimolar Spd added to their diet increased lifespan and reinforced oxidative resilience. The present study is aimed to assess the anti-aging effects of spermidine supplementation at concentrations of 0.1 and 1 mM in honey bees, focusing on autophagy and associated epigenetic changes. Results showed a more pronounced effect at the lower Spd concentration, primarily in the abdomen. Spd induced site-specific histone 3 hypoacetylation at sites K18 and 27, hyperacetylation at K9, with no change at K14 in the entire body. Additionally, autophagy-related genes (ATG3, 5, 9, 13) and genes associated with epigenetic changes (HDAC1, HDAC3, SIRT1, KAT2A, KAT6B, P300, DNMT1A, DNMT1B) were upregulated in the abdomens of honey bees. In conclusion, our findings highlight profound epigenetic changes and autophagy promotion due to spermidine supplementation, contributing to increased honey bee longevity. Further research is needed to fully understand the precise mechanisms and the interplay between epigenetic alterations and autophagy in honey bees, underscoring the significance of autophagy as a geroprotective mechanism.
    DOI:  https://doi.org/10.1371/journal.pone.0306430
  38. Geroscience. 2024 Jul 02.
    Extended lifespan in female Drosophila melanogaster through late-life calorie restriction.
    Michael Li, Jacob Macro, Billy J Huggins, Kali Meadows, Dushyant Mishra, Dominique Martin, Kavitha Kannan, Blanka Rogina.
      Calorie restriction has many beneficial effects on healthspan and lifespan in a variety of species. However, how late in life application of caloric restriction can extend fly life is not clear. Here we show that late-life calorie restriction increases lifespan in female Drosophila melanogaster aged on a high-calorie diet. This shift results in rapid decrease in mortality rate and extends fly lifespan. In contrast, shifting female flies from a low- to a high-calorie diet leads to a rapid increase in mortality and shorter lifespan. These changes are mediated by immediate metabolic and physiological adaptations. One of such adaptation is rapid adjustment in egg production, with flies directing excess energy towards egg production when shifted to a high diet, or away from reproduction in females shifted to low-caloric diet. However, lifelong female fecundity reveals no associated fitness cost due to CR when flies are shifted to a high-calorie diet. In view of high conservation of the beneficial effects of CR on physiology and lifespan in a wide variety of organisms, including humans, our findings could provide valuable insight into CR applications that could provide health benefits later in life.
    Keywords:   Drosophila melanogaster ; Aging; Caloric restriction; Life extension; Lifespan
    DOI:  https://doi.org/10.1007/s11357-024-01233-w
  39. bioRxiv. 2024 Jun 22. pii: 2024.06.18.599640. [Epub ahead of print]
    Full-length direct RNA sequencing reveals extensive remodeling of RNA expression, processing and modification in aging Caenorhabditis elegans.
    Erin C Schiksnis, Ian A Nicastro, Amy E Pasquinelli.
      Organismal aging is marked by decline in cellular function and anatomy, ultimately resulting in death. To inform our understanding of the mechanisms underlying this degeneration, we performed standard RNA sequencing and Nanopore direct RNA sequencing over an adult time course in Caenorhabditis elegans. Long reads allowed for identification of hundreds of novel isoforms and age-associated differential isoform accumulation, resulting from alternative splicing and terminal exon choice. Genome-wide analysis reveals a decline in RNA processing fidelity and a rise in inosine and pseudouridine editing events in transcripts from older animals. In this first map of pseudouridine modifications for C. elegans , we find that they largely reside in coding sequences and that the number of genes with this modification increases with age. Collectively, this analysis discovers transcriptomic signatures associated with age and is a valuable resource to understand the many processes that dictate altered gene expression patterns and post-transcriptional regulation in aging.
    DOI:  https://doi.org/10.1101/2024.06.18.599640
  40. Biomaterials. 2024 Jun 28. pii: S0142-9612(24)00217-5. [Epub ahead of print]311 122683
    Multifunctional scaffolds for bone repair following age-related biological decline: Promising prospects for smart biomaterial-driven technologies.
    Jonathan D Schwartzman, Max McCall, Yasmine Ghattas, Abinaya Sindu Pugazhendhi, Fei Wei, Christopher Ngo, Jonathan Ruiz, Sudipta Seal, Melanie J Coathup.
      The repair of large bone defects due to trauma, disease, and infection can be exceptionally challenging in the elderly. Despite best clinical practice, bone regeneration within contemporary, surgically implanted synthetic scaffolds is often problematic, inconsistent, and insufficient where additional osteobiological support is required to restore bone. Emergent smart multifunctional biomaterials may drive important and dynamic cellular crosstalk that directly targets, signals, stimulates, and promotes an innate bone repair response following age-related biological decline and when in the presence of disease or infection. However, their role remains largely undetermined. By highlighting their mechanism/s and mode/s of action, this review spotlights smart technologies that favorably align in their conceivable ability to directly target and enhance bone repair and thus are highly promising for future discovery for use in the elderly. The four degrees of interactive scaffold smartness are presented, with a focus on bioactive, bioresponsive, and the yet-to-be-developed autonomous scaffold activity. Further, cell- and biomolecular-assisted approaches were excluded, allowing for contemporary examination of the capabilities, demands, vision, and future requisites of next-generation biomaterial-induced technologies only. Data strongly supports that smart scaffolds hold significant promise in the promotion of bone repair in patients with a reduced osteobiological response. Importantly, many techniques have yet to be tested in preclinical models of aging. Thus, greater clarity on their proficiency to counteract the many unresolved challenges within the scope of aging bone is highly warranted and is arguably the next frontier in the field. This review demonstrates that the use of multifunctional smart synthetic scaffolds with an engineered strategy to circumvent the biological insufficiencies associated with aging bone is a viable route for achieving next-generation therapeutic success in the elderly population.
    DOI:  https://doi.org/10.1016/j.biomaterials.2024.122683
  41. Ecotoxicol Environ Saf. 2024 Jul 02. pii: S0147-6513(24)00726-7. [Epub ahead of print]281 116650
    Differential effects of long- and short-term exposure to PM2.5 on accelerating telomere shortening: from in vitro to epidemiological studies.
    Ju Chang-Chien, Ming-Ling Kuo, Yu-Lung Tseng, Hsin-Yi Huang, Hui-Ju Tsai, Tsung-Chieh Yao.
      Exposure to air pollutants has been associated with DNA damage and increases the risks of respiratory diseases, such as asthma and COPD; however short- and long-term effects of air pollutants on telomere dysfunction remain unclear. We investigated the impact of short- and long-term exposure to fine particulate matter with an aerodynamic diameter below 2.5 μm (PM2.5) on telomere length in human bronchial epithelial BEAS-2B cells, and assessed the potential correlation between PM2.5 exposure and telomere length in the LIGHTS childhood cohort study. We observed that long-term, but not short-term, PM2.5 exposure was significantly associated with telomere shortening, along with the downregulation of human telomerase reverse transcriptase (hTERT) mRNA and protein levels. Moreover, long-term exposure to PM2.5 induced proinflammatory cytokine secretion, notably interleukin 6 (IL-6) and IL-8, triggered subG1 cell cycle arrest, and ultimately caused cell death. Long-term exposure to PM2.5 upregulated the LC3-II/ LC3-I ratio but led to p62 protein accumulation in BEAS-2B cells, suggesting a blockade of autophagic flux. Moreover, consistent with our in vitro findings, our epidemiological study found significant association between annual average exposure to higher PM2.5 and shortening of leukocyte telomere length in children. However, no significant association between 7-day short-term exposure to PM2.5 and leukocyte telomere length was observed in children. By combining in vitro experimental and epidemiological studies, our findings provide supportive evidence linking potential regulatory mechanisms to population level with respect to long-term PM2.5 exposure to telomere shortening in humans.
    Keywords:  Long-term exposure; Particulate matter; Short-term exposure; Telomerase; Telomere length
    DOI:  https://doi.org/10.1016/j.ecoenv.2024.116650
  42. Free Radic Res. 2024 Jul 01. 1-12
    The impact of aerobic exercise timing on BMAL1 protein expression and antioxidant responses in skeletal muscle of mice.
    Lei Xu, Jie Jia, Jingjing Yu, Shudan Miao, Ying Zhang.
      It is well known that the adaptations of muscular antioxidant system to aerobic exercise depend on the frequency, intensity, duration, type of the exercise. Nonetheless, the timing of aerobic exercise, related to circadian rhythms or biological clock, may also affect the antioxidant defense system, but its impact remains uncertain. Bain and muscle ARNT-like 1 (BMAL1) is the core orchestrator of molecular clock, which can maintain cellular redox homeostasis by directly controlling the transcriptional activity of nuclear factor erythroid 2-related factor 2 (NRF2). So, our research objective was to evaluate the impacts of aerobic exercise training at various time points of the day on BMAL1 and NRF2-mediated antioxidant system in skeletal muscle. C57BL/6J mice were assigned to the control group, the group exercising at Zeitgeber Time 12 (ZT12), and the group exercising at ZT24. Control mice were not intervened, while ZT12 and ZT24 mice were trained for four weeks at the early and late time point of their active phase, respectively. We observed that the skeletal muscle of ZT12 mice exhibited higher total antioxidant capacity and lower reactive oxygen species compared to ZT24 mice. Furthermore, ZT12 mice improved the colocalization of BMAL1 with nucleus, the protein expression of BMAL1, NRF2, NAD(P)H quinone oxidoreductase 1, heme oxygenase 1, glutamate-cysteine ligase modifier subunit and glutathione reductase in comparison to those of ZT24 mice. In conclusion, the 4-week aerobic training performed at ZT12 is more effective for enhancing NRF2-mediated antioxidant responses of skeletal muscle, which may be attributed to the specific activation of BMAL1.
    Keywords:  BMAL1; Exercise timing; NRF2-mediated antioxidant responses; skeletal muscle
    DOI:  https://doi.org/10.1080/10715762.2024.2348789
  43. J Dermatol Sci. 2024 Jun 18. pii: S0923-1811(24)00132-4. [Epub ahead of print]
    Topical application of a BCL-2 inhibitor ameliorates imiquimod-induced psoriasiform dermatitis by eliminating senescent cells.
    Huan Zhu, Jiao Jiang, Ming Yang, Mingming Zhao, Zhenghao He, Congli Tang, Cailing Song, Ming Zhao, Arne N Akbar, Venkat Reddy, Wenjing Pan, Song Li, Yixin Tan, Haijing Wu, Qianjin Lu.
       BACKGROUND: Psoriasis is an inflammatory skin disease with unclear pathogenesis and unmet therapeutic needs.
    OBJECTIVE: To investigate the role of senescent CD4+ T cells in psoriatic lesion formation and explore the application of senolytics in treating psoriasis.
    METHODS: We explored the expression levels of p16INK4a and p21, classical markers of cellular senescence, in CD4+ T cells from human psoriatic lesions and imiquimod (IMQ)-induced psoriatic lesions. We prepared a senolytic gel using B-cell lymphoma 2 (BCL-2) inhibitor ABT-737 and evaluated its therapeutic efficacy in treating psoriasis.
    RESULTS: Using multispectrum immunohistochemistry (mIHC) staining, we detected increased expression levels of p16INK4a and p21 in CD4+ T cells from psoriatic lesions. After topical application of ABT-737 gel, significant alleviation of IMQ-induced psoriatic lesions was observed, with milder pathological alterations. Mechanistically, ABT-737 gel significantly decreased the percentage of senescent cells, expression of T cell receptor (TCR) α and β chains, and expression of Tet methylcytosine dioxygenase 2 (Tet2) in IMQ-induced psoriatic lesions, as determined by mIHC, high-throughput sequencing of the TCR repertoire, and RT-qPCR, respectively. Furthermore, the severity of psoriatic lesions in CD4creTet2f/f mice was milder than that in Tet2f/f mice in the IMQ-induced psoriasis model.
    CONCLUSION: We revealed the roles of senescent CD4+ T cells in developing psoriasis and highlighted the therapeutic potential of topical ABT-737 gel in treating psoriasis through the elimination of senescent cells, modulation of the TCR αβ repertoire, and regulation of the TET2-Th17 cell pathway.
    Keywords:  BCL-2 inhibitor; Cellular senescence; Psoriasis; Senolytics
    DOI:  https://doi.org/10.1016/j.jdermsci.2024.06.002
  44. Cell Biol Int. 2024 Jul 02.
    Golgi protein ACBD3 downregulation sensitizes cells to ferroptosis.
    Ying Qian, Shanchuan Ma, Rong Qiu, Zhiyang Sun, Wei Liu, Fan Wu, Sin Man Lam, Zhengguo Xia, Kezhen Wang, Linshen Fang, Guanghou Shui, Xinwang Cao.
      Ferroptosis, a form of cell death driven by iron-dependent lipid peroxidation, is emerging as a promising target in cancer therapy. It is regulated by a network of molecules and pathways that modulate lipid metabolism, iron homeostasis and redox balance, and related processes. However, there are still numerous regulatory molecules intricately involved in ferroptosis that remain to be identified. Here, we indicated that suppression of Golgi protein acyl-coenzyme A binding domain A containing 3 (ACBD3) increased the sensitivity of Henrieta Lacks and PANC1 cells to ferroptosis. ACBD3 knockdown increases labile iron levels by promoting ferritinophagy. This increase in free iron, coupled with reduced levels of glutathione peroxidase 4 due to ACBD3 knockdown, leads to the accumulation of reactive oxygen species and lipid peroxides. Moreover, ACBD3 knockdown also results in elevated levels of polyunsaturated fatty acid-containing glycerophospholipids through mechanisms that remain to be elucidated. Furthermore, inhibition of ferrtinophagy in ACBD3 downregulated cells by knocking down the nuclear receptor co-activator 4 or Bafilomycin A1 treatment impeded ferroptosis. Collectively, our findings highlight the pivotal role of ACBD3 in governing cellular resistance to ferroptosis and suggest that pharmacological manipulation of ACBD3 levels is a promising strategy for cancer therapy.
    Keywords:  ACBD3; PUFA‐PLs; ferritinophagy; ferroptosis; iron homeostasis
    DOI:  https://doi.org/10.1002/cbin.12213
  45. Z Naturforsch C J Biosci. 2024 Jul 05.
    Coenzyme Q10 supplementation affects cellular ionic balance: relevance to aging.
    Parisha Srivastava, Sukanya Bhoumik, Arun K Yadawa, Rashmi Kesherwani, Syed Ibrahim Rizvi.
      Aging results into disruptive physiological functioning and cellular processes that affect the composition and structure of the plasma membrane. The plasma membrane is the major regulator of ionic homeostasis that regulates the functioning of membrane transporters and exchangers. Coenzyme Q10 is a lipid-soluble antioxidant molecule that declines during aging and age-associated diseases. The present study aims to explore the role of Coenzyme Q10 supplementation to rats during aging on membrane transporters and redox biomarkers. The study was conducted on young and old male Wistar rats supplemented with 20 mg/kg b.w. of Coenzyme Q10 per day. After a period of 28 days, rats were sacrificed and erythrocyte membrane was isolated. The result exhibits significant decline in biomarkers of oxidative stress in old control rats when compared with young control. The effect of Coenzyme Q10 supplementation was more pronounced in old rats. The functioning of membrane transporters and Na+/H+ exchanger showed potential return to normal levels in the Coenzyme Q10 treated rats. Overall, the results demonstrate that Coenzyme Q10 plays an important role in maintaining redox balance in cells which interconnects with membrane integrity. Thus, Coenzyme Q10 supplementation may play an important role in protecting age related alterations in erythrocyte membrane physiology.
    Keywords:  Coenzyme Q10; aging; ionic balance; membrane transporters; oxidative stress
    DOI:  https://doi.org/10.1515/znc-2024-0129
  46. bioRxiv. 2024 Jun 22. pii: 2024.06.21.597078. [Epub ahead of print]
    Coaching ribosome biogenesis from the nuclear periphery.
    Yinyin Zhuang, Xiangfu Guo, Olga V Razorenova, Christopher E Miles, Wenting Zhao, Xiaoyu Shi.
      Severe invagination of the nuclear envelope is a hallmark of cancers, aging, neurodegeneration, and infections. However, the outcomes of nuclear invagination remain unclear. This work identified a new function of nuclear invagination: regulating ribosome biogenesis. With expansion microscopy, we observed frequent physical contact between nuclear invaginations and nucleoli. Surprisingly, the higher the invagination curvature, the more ribosomal RNA and pre-ribosomes are made in the contacted nucleolus. By growing cells on nanopillars that generate nuclear invaginations with desired curvatures, we can increase and decrease ribosome biogenesis. Based on this causation, we repressed the ribosome levels in breast cancer and progeria cells by growing cells on low-curvature nanopillars, indicating that overactivated ribosome biogenesis can be rescued by reshaping nuclei. Mechanistically, high-curvature nuclear invaginations reduce heterochromatin and enrich nuclear pore complexes, which promote ribosome biogenesis. We anticipate that our findings will serve as a foundation for further studies on nuclear deformation.
    Highlights: Nuclear invaginations regulate ribosome biogenesis by physically contacting nucleoli.High-curvature nuclear tunnels increase ribosome biogenesis.Nanopillars reduce ribosome biogenesis by transforming high-curvature nuclear invaginations to low-curvature ones.
    DOI:  https://doi.org/10.1101/2024.06.21.597078
  47. Adv Gerontol. 2024 ;37(1-2): 21-25
    [Novel integrative multi-omics strategies of human's biological age computation.]
    I A Solovev.
      Multi-omics methods for analysing postgenomic data have become firmly established in the tools of molecular gerontology only in recent years, since previously there were no comprehensive integrative approaches adequate to the task of calculating biological age. This paper provides an overview of existing papers on multi-omics integrative approaches in calculating the biological age of a human. An analysis of the most common options for integrating methylomic, transcriptomic, proteomic, microbiomic and metabolomic datasets was carried out. We defined (1) concatenation (machine learning), in which models are developed using a concatenated data matrix, formed by combining multiple omics data sets; (2) fusion model approaches that create multiple intermediate submodels for different omics data to then build a final integrated model from the various intermediate submodels; and (3) transformation methods (via artificial intelligence) that first transform each of the single omics data sets into core plots or matrices, and then combine them all into one graph before building an integral complex model. It is unlikely that multi-omics approaches will find application in anti-aging personalized medicine, but they will undoubtedly deepen and expand the understanding of the fundamental processes standing behind the phenomenon of the biological aging clocks.
    Keywords:  aging; bioinformatics; biological age; machine learning; multi-omics approaches
  48. Nat Genet. 2024 Jul 01.
    Mitochondrial genetics through the lens of single-cell multi-omics.
    Lena Nitsch, Caleb A Lareau, Leif S Ludwig.
      Mitochondria carry their own genetic information encoding for a subset of protein-coding genes and translational machinery essential for cellular respiration and metabolism. Despite its small size, the mitochondrial genome, its natural genetic variation and molecular phenotypes have been challenging to study using bulk sequencing approaches, due to its variation in cellular copy number, non-Mendelian modes of inheritance and propensity for mutations. Here we highlight emerging strategies designed to capture mitochondrial genetic variation across individual cells for lineage tracing and studying mitochondrial genetics in primary human cells and clinical specimens. We review recent advances surrounding single-cell mitochondrial genome sequencing and its integration with functional genomic readouts, including leveraging somatic mitochondrial DNA mutations as clonal markers that can resolve cellular population dynamics in complex human tissues. Finally, we discuss how single-cell whole mitochondrial genome sequencing approaches can be utilized to investigate mitochondrial genetics and its contribution to cellular heterogeneity and disease.
    DOI:  https://doi.org/10.1038/s41588-024-01794-8
  49. Mol Aspects Med. 2024 Jul 01. pii: S0098-2997(24)00050-5. [Epub ahead of print]98 101291
    Frailty and biological age. Which best describes our aging and longevity?
    Judith Félix, Irene Martínez de Toda, Estefanía Díaz-Del Cerro, Mónica González-Sánchez, Mónica De la Fuente.
      Frailty and Biological Age are two closely related concepts; however, frailty is a multisystem geriatric syndrome that applies to elderly subjects, whereas biological age is a gerontologic way to describe the rate of aging of each individual, which can be used from the beginning of the aging process, in adulthood. If frailty reaches less consensus on the definition, it is a term much more widely used than this of biological age, which shows a clearer definition but is scarcely employed in social and medical fields. In this review, we suggest that this Biological Age is the best to describe how we are aging and determine our longevity, and several examples support our proposal.
    Keywords:  Aging; Biological age; Frailty; Geriatrics; Gerontology; Longevity
    DOI:  https://doi.org/10.1016/j.mam.2024.101291
  50. PLoS Genet. 2024 Jul 02. 20(7): e1011341
    REV3 promotes cellular tolerance to 5-fluorodeoxyuridine by activating translesion DNA synthesis and intra-S checkpoint.
    Mubasshir Washif, Ryotaro Kawasumi, Kouji Hirota.
      The drug floxuridine (5-fluorodeoxyuridine, FUdR) is an active metabolite of 5-Fluorouracil (5-FU). It converts to 5-fluorodeoxyuridine monophosphate (FdUMP) and 5-fluorodeoxyuridine triphosphate (FdUTP), which on incorporation into the genome inhibits DNA replication. Additionally, it inhibits thymidylate synthase, causing dTMP shortage while increasing dUMP availability, which induces uracil incorporation into the genome. However, the mechanisms underlying cellular tolerance to FUdR are yet to be fully elucidated. In this study, we explored the mechanisms underlying cellular resistance to FUdR by screening for FUdR hypersensitive mutants from a collection of DT40 mutants deficient in each genomic maintenance system. We identified REV3, which is involved in translesion DNA synthesis (TLS), to be a critical factor in FUdR tolerance. Replication using a FUdR-damaged template was attenuated in REV3-/- cells, indicating that the TLS function of REV3 is required to maintain replication on the FUdR-damaged template. Notably, FUdR-exposed REV3-/- cells exhibited defective cell cycle arrest in the early S phase, suggesting that REV3 is involved in intra-S checkpoint activation. Furthermore, REV3-/- cells showed defects in Chk1 phosphorylation, which is required for checkpoint activation, but the survival of FUdR-exposed REV3-/- cells was further reduced by the inhibition of Chk1 or ATR. These data indicate that REV3 mediates DNA checkpoint activation at least through Chk1 phosphorylation, but this signal acts in parallel with ATR-Chk1 DNA damage checkpoint pathway. Collectively, we reveal a previously unappreciated role of REV3 in FUdR tolerance.
    DOI:  https://doi.org/10.1371/journal.pgen.1011341
  51. Int J Biol Macromol. 2024 Jun 29. pii: S0141-8130(24)04328-9. [Epub ahead of print]275(Pt 1): 133523
    Discovery of baicalein derivatives as novel inhibitors against human pancreatic lipase: Structure-activity relationships and inhibitory mechanisms.
    Xiao-Ya Qin, Rong Zhu, Xu-Dong Hou, Guang-Hao Zhu, Min Zhang, Yu-Fan Fan, Sheng-Lan Qi, Jian Huang, Hui Tang, Ping Wang, Guang-Bo Ge.
      Human pancreatic lipase (hPL) is a vital digestive enzyme responsible for breaking down dietary fats in humans, inhibiting hPL is a feasible strategy for preventing and treating obesity. This study aims to investigate the structure-activity relationships (SARs) of flavonoids as hPL inhibitors, and to find potent hPL inhibitors from natural and synthetic flavonoids. In this work, the anti-hPL effects of forty-nine structurally diverse naturally occurring flavonoids were assessed and the SARs were summarized. The results demonstrated that the pyrogallol group on the A ring was a key moiety for hPL inhibition. Subsequently, a series of baicalein derivatives were synthesized, while 4'-amino baicalein (ABA) and 4'-pyrrolidine baicalein (PBA) were identified as novel potent hPL inhibitors (IC50 < 1 μM). Further investigations showed that scutellarein, ABA and PBA potently inhibited hPL in a non-competitive manner (Ki < 1 μM). Among all tested flavonoids, PBA showed the most potent anti-hPL effect in vitro, while this agent also exhibited favorable safety profiles, unique tissue distribution (high exposure level to intestinal system but low exposure levels to deep organs) and impressive in vivo effects for lowering blood triglyceride levels in mice. Collectively, this work uncovers the SARs of flavonoids against hPL, while a newly synthetic flavonoid (PBA) emerges as a potent hPL inhibitor with favorable safety profiles and impressive anti-hPL effects in vivo.
    Keywords:  Flavonoids; Human pancreatic lipase (hPL); Inhibitory mechanism; Obesity; SAR
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.133523
  52. Cell Mol Gastroenterol Hepatol. 2024 Jul 03. pii: S2352-345X(24)00131-0. [Epub ahead of print] 101376
    Inhibition of EZH2 Reduces Aging-Related Decline in Interstitial Cells of Cajal of the Mouse Stomach.
    Negar Taheri, Egan L Choi, Vy Truong Thuy Nguyen, Yuebo Zhang, Nick M Huynh, Todd A Kellogg, Andre J van Wijnen, Tamas Ordog, Yujiro Hayashi.
       BACKGROUND & AIMS: Restricted gastric motor functions contribute to aging-associated under-nutrition, sarcopenia, and frailty. We previously identified a decline in interstitial cells of Cajal (ICC, gastrointestinal pacemaker and neuromodulator cells) and their stem cells (ICC-SC) as a key factor of gastric aging. Altered functionality of the histone methyltransferase enhancer of zeste homolog 2 (EZH2) is central to organismal aging. Here, we investigated the role of EZH2 in the aging-related loss of ICC/ICC-SC.
    METHODS: klotho mice, a model of accelerated aging, were treated with the most clinically advanced EZH2 inhibitor, EPZ6438 (tazemetostat; 160 mg/kg i.p. BID for 3 weeks). Gastric ICC were analyzed by western blotting (WB) and immunohistochemistry. ICC and ICC-SC were quantified by flow cytometry. Gastric slow wave activity was assessed by intracellular electrophysiology. Ezh2 was deactivated in ICC by treating KitcreERT2/+;Ezh2fl/fl mice with tamoxifen. TRP53, a key mediator of aging-related ICC loss, was induced with nutlin 3a in gastric muscle organotypic cultures and an ICC-SC line.
    RESULTS: In klotho mice, EPZ6438 treatment mitigated the decline in the ICC growth factor KIT ligand/stem cell factor and gastric ICC. EPZ6438 also improved gastric slow wave activity and mitigated the reduced food intake and impaired body weight gain characteristic of this strain. Conditional genomic deletion of Ezh2 in Kit-expressing cells also prevented ICC loss. In organotypic cultures and ICC-SC, EZH2 inhibition prevented the aging-like effects of TRP53 stabilization on ICC/ICC-SC.
    CONCLUSIONS: Inhibition of EZH2 with EPZ6438 mitigates aging-related ICC/ICC-SC loss and gastric motor dysfunction, improving slow wave activity and food intake in klotho mice.
    Keywords:  Ezh2(fl/fl); Kit(creERT2/+); food intake; gastric motility; klotho
    DOI:  https://doi.org/10.1016/j.jcmgh.2024.101376
  53. Chem Rec. 2024 Jul 02. e202300369
    Advances in pH Sensing: From Traditional Approaches to Next-Generation Sensors in Biological Contexts.
    Mahmood Hassan Akhtar, Muhammad Azhar Hayat Nawaz, Manzar Abbas, Ning Liu, Wenzhao Han, Yan Lv, Cong Yu.
      pH has been considered one of the paramount factors in bodily functions because most cellular tasks exclusively rely on precise pH values. In this context, the current techniques for pH sensing provide us with the futuristic insight to further design therapeutic and diagnostic tools. Thus, pH-sensing (electrochemically and optically) is rapidly evolving toward exciting new applications and expanding researchers' interests in many chemical contexts, especially in biomedical applications. The adaptation of cutting-edge technology is subsequently producing the modest form of these biosensors as wearable devices, which are providing us the opportunity to target the real-time collection of vital parameters, including pH for improved healthcare systems. The motif of this review is to provide insight into trending tech-based systems employed in real-time or in-vivo pH-responsive monitoring. Herein, we briefly go through the pH regulation in the human body to help the beginners and scientific community with quick background knowledge, recent advances in the field, and pH detection in real-time biological applications. In the end, we summarize our review by providing an outlook; challenges that need to be addressed, and prospective integration of various pH in vivo platforms with modern electronics that can open new avenues of cutting-edge techniques for disease diagnostics and prevention.
    Keywords:  fluorophores; microelectrode; pH regulation; pH sensing; wearable sensor
    DOI:  https://doi.org/10.1002/tcr.202300369
  54. bioRxiv. 2024 Jun 18. pii: 2024.06.17.599259. [Epub ahead of print]
    Vimentin promotes collective cell migration through collagen networks via increased matrix remodeling and spheroid fluidity.
    Minh Tri Ho Thanh, Arun Poudel, Shabeeb Ameen, Bobby Carroll, M Wu, Pranav Soman, Tao Zhang, J M Schwarz, Alison E Patteson.
      The intermediate filament (IF) protein vimentin is associated with many diseases with phenotypes of enhanced cellular migration and aggressive invasion through the extracellular matrix (ECM) of tissues, but vimentin's role in in-vivo cell migration is still largely unclear. Vimentin is important for proper cellular adhesion and force generation, which are critical to cell migration; yet the vimentin cytoskeleton also hinders the ability of cells to squeeze through small pores in ECM, resisting migration. To identify the role of vimentin in collective cell migration, we generate spheroids of wide-type and vimentin-null mouse embryonic fibroblasts (mEFs) and embed them in a 3D collagen matrix. We find that loss of vimentin significantly impairs the ability of the spheroid to collectively expand through collagen networks and remodel the collagen network. Traction force analysis reveals that vimentin null spheroids exert less contractile force than their wild-type counterparts. In addition, spheroids made of mEFs with only vimentin unit length filaments (ULFs) exhibit similar behavior as vimentin-null spheroids, suggesting filamentous vimentin is required to promote 3D collective cell migration. We find the vimentin-mediated collective cell expansion is dependent on matrix metalloproteinase (MMP) degradation of the collagen matrix. Further, 3D vertex model simulation of spheroid and embedded ECM indicates that wild-type spheroids behave more fluid-like, enabling more active pulling and reconstructing the surrounding collagen network. Altogether, these results signify that VIF plays a critical role in enhancing migratory persistence in 3D matrix environments through MMP transportation and tissue fluidity.
    DOI:  https://doi.org/10.1101/2024.06.17.599259
  55. Genome Med. 2024 Jul 02. 16(1): 85
    An expedited screening platform for the discovery of anti-ageing compounds in vitro and in vivo.
    Celia Lujan, Eleanor Jane Tyler, Simone Ecker, Amy Philomena Webster, Eleanor Rachel Stead, Victoria Eugenia Martinez-Miguel, Deborah Milligan, James Charles Garbe, Martha Ruskin Stampfer, Stephan Beck, Robert Lowe, Cleo Lucinda Bishop, Ivana Bjedov.
       BACKGROUND: Restraining or slowing ageing hallmarks at the cellular level have been proposed as a route to increased organismal lifespan and healthspan. Consequently, there is great interest in anti-ageing drug discovery. However, this currently requires laborious and lengthy longevity analysis. Here, we present a novel screening readout for the expedited discovery of compounds that restrain ageing of cell populations in vitro and enable extension of in vivo lifespan.
    METHODS: Using Illumina methylation arrays, we monitored DNA methylation changes accompanying long-term passaging of adult primary human cells in culture. This enabled us to develop, test, and validate the CellPopAge Clock, an epigenetic clock with underlying algorithm, unique among existing epigenetic clocks for its design to detect anti-ageing compounds in vitro. Additionally, we measured markers of senescence and performed longevity experiments in vivo in Drosophila, to further validate our approach to discover novel anti-ageing compounds. Finally, we bench mark our epigenetic clock with other available epigenetic clocks to consolidate its usefulness and specialisation for primary cells in culture.
    RESULTS: We developed a novel epigenetic clock, the CellPopAge Clock, to accurately monitor the age of a population of adult human primary cells. We find that the CellPopAge Clock can detect decelerated passage-based ageing of human primary cells treated with rapamycin or trametinib, well-established longevity drugs. We then utilise the CellPopAge Clock as a screening tool for the identification of compounds which decelerate ageing of cell populations, uncovering novel anti-ageing drugs, torin2 and dactolisib (BEZ-235). We demonstrate that delayed epigenetic ageing in human primary cells treated with anti-ageing compounds is accompanied by a reduction in senescence and ageing biomarkers. Finally, we extend our screening platform in vivo by taking advantage of a specially formulated holidic medium for increased drug bioavailability in Drosophila. We show that the novel anti-ageing drugs, torin2 and dactolisib (BEZ-235), increase longevity in vivo.
    CONCLUSIONS: Our method expands the scope of CpG methylation profiling to accurately and rapidly detecting anti-ageing potential of drugs using human cells in vitro, and in vivo, providing a novel accelerated discovery platform to test sought after anti-ageing compounds and geroprotectors.
    Keywords:  Ageing; CellPopAge epigenetic Clock; CpG methylation; Drug discovery; Rapamycin; Senescence
    DOI:  https://doi.org/10.1186/s13073-024-01349-w
  56. Indian J Orthop. 2024 Jul;58(7): 932-943
    A Gelatin-Based Biomimetic Scaffold Promoting Osteogenic Differentiation of Adipose-Derived Mesenchymal Stem Cells.
    Anjitha S Prasad, S Banu, S Silpa Das, Lynda V Thomas.
       Background: In bone tissue engineering segment, numerous approaches have been investigated to address critically sized bone defects via 3D scaffolds, as the amount of autologous bone grafts are limited, accompanied with complications on harvesting. Moreover, the use of bone-marrow-derived stem cells is also a limiting factor owing to the invasive procedures involved and the low yield of stem cells. Hence, research is ongoing on the search for an ideal bone graft system promoting bone growth and regeneration.
    Purpose of the Study: This study aims to develop a unique platform for tissue development via stem cell differentiation towards an osteogenic phenotype providing optimum biological cues for cell adhesion, differentiation and proliferation using biomimetic gelatin-based scaffolds. The use of adipose-derived mesenchymal stem cells in this study also offers an ideal approach for the development of an autologous bone graft.
    Methods: A gelatin-vinyl acetate-based 3D scaffold system incorporating Bioglass was developed and the osteogenic differentiation of adipose-derived mesenchymal stem cells (ADMSCs) on the highly porous freeze-dried gelatin-vinyl acetate/ Bioglass scaffold (GB) system was analyzed. The physicochemical properties, cell proliferation and viability were investigated by seeding rat adipose tissue-derived mesenchymal stem cells (ADSCs) onto the scaffolds. The osteogenic differentiation potential of the ADMSC seeded GeVAc/bioglass system was assessed using calcium deposition assay and bone-related protein and genes and comparing with the 3D Gelatin vinyl acetate coppolymer (GeVAc) constructs.
    Results and Conclusion: According to the findings, the 3D porous GeVAc/bioglass scaffold can be considered as a promising matrix for bone tissue regeneration and the 3D architecture supports the differentiation of the ADMSCs into osteoblast cells and enhances the production of mineralized bone matrix.
    Keywords:  Adipose-derived mesenchymal stem cells; Bioglass; Bone tissue engineering; Freeze-dried scaffold; Gelatin-vinyl acetate; Osteogenic differentiation
    DOI:  https://doi.org/10.1007/s43465-024-01182-8
  57. Eye (Lond). 2024 Jul 04.
    Robotising vitreoretinal surgeries.
    Helen Mi, Robert E MacLaren, Jasmina Cehajic-Kapetanovic.
      The use of robotic surgery in ophthalmology has been shown to offer many potential advantages to current surgical techniques. Vitreoretinal surgery requires complex manoeuvres and high precision, and this is an area that exceeds manual human dexterity in certain surgical situations. With the advent of advanced therapeutics such as subretinal gene therapy, precise delivery and minimising trauma is imperative to optimize outcomes. There are multiple robotic systems in place for ophthalmology in pre-clinical and clinical use, and the Preceyes Robotic Surgical System (Preceyes BV) has also gained the CE mark and is commercially available for use. Recent in-vivo and in-human surgeries have been performed successfully with robotics systems. This includes membrane peeling, subretinal injections of therapeutics, and retinal vein cannulation. There is huge potential to integrate robotic surgery into mainstream clinical practice. In this review, we summarize the existing systems, and clinical implementation so far, and highlight the future clinical applications for robotic surgery in vitreo-retina.
    DOI:  https://doi.org/10.1038/s41433-024-03149-3
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