bims-caglex Biomed News
on Cellular aging and life extension
Issue of 2024–01–28
77 papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño
  1. ResnetAge: A Resnet-Based DNA Methylation Age Prediction Method.
  2. Mitochondrial-related microRNAs and their roles in cellular senescence.
  3. Rapamycin functionalized carbon Dots: Target-oriented synthesis and suppression of vascular cell senescence.
  4. Epigenetic Reprogramming as a Key to Reverse Ageing and Increase Longevity.
  5. The Potential of Using Cochayuyo (Durvillaea incurvata) Extract Obtained by Ultrasound-Assisted Extraction to Fight against Aging-Related Diseases.
  6. Endothelial Cell Aging and Autophagy Dysregulation.
  7. Hesperetin activates CISD2 to attenuate senescence in human keratinocytes from an older person and rejuvenates naturally aged skin in mice.
  8. Fisetin suppresses chondrocyte senescence and attenuates osteoarthritis progression by targeting sirtuin 6.
  9. Biological Aging Acceleration Due to Environmental Exposures: An Exciting New Direction in Toxicogenomics Research.
  10. The Dynamic SUMOylation Changes and Their Potential Role in the Senescence of APOE4 Mice.
  11. The Impact of Long Noncoding RNAs in Tissue Regeneration and Senescence.
  12. Type 2 cytokine signaling in macrophages protects from cellular senescence and organismal aging.
  13. Biological aging markers in blood and brain tissue indicate age acceleration in alcohol use disorder.
  14. Development of an epigenetic clock to predict visual age progression of human skin.
  15. Red Ginseng Attenuates the Hepatic Cellular Senescence in Aged Mice.
  16. Primary oocytes with cellular senescence features are involved in ovarian aging in mice.
  17. Revisiting sensitivity of senescent cells to BH3 mimetics.
  18. Vutiglabridin Alleviates Cellular Senescence with Metabolic Regulation and Circadian Clock in Human Dermal Fibroblasts.
  19. Humanization of the mouse telomerase gene reset telomeres to human length.
  20. The mixed effect of Endocrine-Disrupting chemicals on biological age Acceleration: Unveiling the mechanism and potential intervention target.
  21. TXNRD1 drives the innate immune response in senescent cells with implications for age-associated inflammation.
  22. The Possible Roles of β-alanine and L-carnosine in Anti-aging.
  23. Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Rescue Testicular Aging.
  24. Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction.
  25. Screening of Biomarkers Associated with Osteoarthritis Aging Genes and Immune Correlation Studies.
  26. PICLS with human cells is the first high throughput screening method for identifying novel compounds that extend lifespan.
  27. Neuronal microstructural changes in the human brain are associated with neurocognitive aging.
  28. SA-β-Gal in Kidney Tubules as a Predictor of Renal Outcome in Patients with Chronic Kidney Disease.
  29. Chitosan alleviates ovarian aging by enhancing macrophage phagocyte-mediated tissue homeostasis.
  30. Age-related secretion of grancalcin by macrophages induces skeletal stem/progenitor cell senescence during fracture healing.
  31. Molecular Network Mechanism Analysis of Urine Stem Cells Against Retinal Aging.
  32. The Binding of HSPA8 and Mitochondrial ALDH2 Mediates Oxygen-Glucose Deprivation-Induced Fibroblast Senescence.
  33. ELF5: A Molecular Clock for Breast Aging and Cancer Susceptibility.
  34. Suppression of Bcl3 Disrupts Viability of Breast Cancer Cells through Both p53-Dependent and p53-Independent Mechanisms via Loss of NF-κB Signalling.
  35. HDAC1/2 inhibitor therapy improves multiple organ systems in aged mice.
  36. Potential Roles of Nr4a3-Mediated Inflammation in Immunological and Neurological Diseases.
  37. RBM10 regulates the tumorigenic potential of human cancer cells by modulating PPM1B and YBX1 activities.
  38. Uncovering the roles of DNA hemi-methylation in transcriptional regulation using MspJI-assisted hemi-methylation sequencing.
  39. Very low-carbohydrate diet with higher protein ratio improves lipid metabolism and inflammation in rats with diet-induced nonalcoholic fatty liver disease.
  40. C2CD4B Evokes Oxidative Stress and Vascular Dysfunction via a PI3K/Akt/PKCα-Signaling Pathway.
  41. PARP1 at the crossroad of cellular senescence and nucleolar processes.
  42. Anti-Aging Drugs and the Related Signal Pathways.
  43. A renal clearable fluorogenic probe for in vivo β-galactosidase activity detection during aging and senolysis.
  44. The Multifaceted Roles of NRF2 in Cancer: Friend or Foe?
  45. (+)-Lipoic acid reduces mitochondrial unfolded protein response and attenuates oxidative stress and aging in an in vitro model of non-alcoholic fatty liver disease.
  46. Pharmacological functions of salidroside in renal diseases: facts and perspectives.
  47. The Trajectory of Successful Aging: Insights from Metagenome and Cytokine Profiling.
  48. Reduced SIRT1 and SIRT3 and Lower Antioxidant Capacity of Seminal Plasma Is Associated with Shorter Sperm Telomere Length in Oligospermic Men.
  49. DNA methylation and chromatin accessibility predict age in the domestic dog.
  50. Heavy Metal Exposure: Molecular Pathways, Clinical Implications, and Protective Strategies.
  51. Methamphetamine use shortens telomere length in male adults and rats.
  52. DDQ anti-aging properties expressed with improved mitophagy in mutant tau HT22 neuronal cells.
  53. Protein-Protein Interactions of Seryl-tRNA Synthetases with Emphasis on Human Counterparts and Their Connection to Health and Disease.
  54. Hallmarks of Aging: Causes and Consequences.
  55. Translatability of mouse muscle-aging for humans: the role of sex.
  56. Exercise-induced expression of genes associated with aging in the hippocampus of rats.
  57. Drug discovery targeting nicotinamide phosphoribosyltransferase (NAMPT): Updated progress and perspectives.
  58. The role of gut microbiota in the occurrence and progression of non-alcoholic fatty liver disease.
  59. Suppressor of cytokine signaling 3-derived peptide as a therapeutic for inflammatory and oxidative stress-induced damage to the retina.
  60. Phosphorylation of Thr-225 and Ser-262 on ERD7 Promotes Age-Dependent and Stress-Induced Leaf Senescence through the Regulation of Hydrogen Peroxide Accumulation in Arabidopsis thaliana.
  61. Glycolysis: an emerging regulator of osteoarthritis.
  62. Immunological dimensions of neuroinflammation and microglial activation: exploring innovative immunomodulatory approaches to mitigate neuroinflammatory progression.
  63. Use of Minimally Invasive Methods to Assess Fuel Utilization and Circadian Rhythms in Older Adults.
  64. Mitochondrial membrane potential regulates nuclear DNA methylation and gene expression through phospholipid remodeling.
  65. Air pollution drives macrophage senescence through a phagolysosome-15-lipoxygenase pathway.
  66. Experimental variables that impact outcomes in Caenorhabditis elegans aging stress response.
  67. Bazi Bushen capsule improves the deterioration of the intestinal barrier function by inhibiting NLRP3 inflammasome-mediated pyroptosis through microbiota-gut-brain axis.
  68. Telomeres: Dysfunction, Maintenance, Aging and Cancer.
  69. Cellular Senescence in Liver Cancer: How Dying Cells Become "Zombie" Enemies.
  70. The integration of multi-omics analysis and machine learning for the identification of prognostic assessment and immunotherapy efficacy through aging-associated genes in lung cancer.
  71. Post-translational modification and mitochondrial function in Parkinson's disease.
  72. A novel macrolide-Del-1 axis to regenerate bone in old age.
  73. Disulfiram: A novel repurposed drug for cancer therapy.
  74. The association between age and telomere length is age-dependent: Evidence for a threshold model of telomere length maintenance.
  75. 6-Shogaol Ameliorates Liver Inflammation and Fibrosis in Mice on a Methionine- and Choline-Deficient Diet by Inhibiting Oxidative Stress, Cell Death, and Endoplasmic Reticulum Stress.
  76. Nuclear Factor Kappa B: A Nobel Therapeutic Target of Flavonoids Against Parkinson's Disease.
  77. Nrf2 Pathway and Oxidative Stress as a Common Target for Treatment of Diabetes and Its Comorbidities.
  1. Bioengineering (Basel). 2023 Dec 28. pii: 34. [Epub ahead of print]11(1):
    ResnetAge: A Resnet-Based DNA Methylation Age Prediction Method.
    Lijuan Shi, Boquan Hai, Zhejun Kuang, Han Wang, Jian Zhao.
      Aging is a significant contributing factor to degenerative diseases such as cancer. The extent of DNA methylation in human cells indicates the aging process and screening for age-related methylation sites can be used to construct epigenetic clocks. Thereby, it can be a new aging-detecting marker for clinical diagnosis and treatments. Predicting the biological age of human individuals is conducive to the study of physical aging problems. Although many researchers have developed epigenetic clock prediction methods based on traditional machine learning and even deep learning, higher prediction accuracy is still required to match the clinical applications. Here, we proposed an epigenetic clock prediction method based on a Resnet neuro networks model named ResnetAge. The model accepts 22,278 CpG sites as a sample input, supporting both the Illumina 27K and 450K identification frameworks. It was trained using 32 public datasets containing multiple tissues such as whole blood, saliva, and mouth. The Mean Absolute Error (MAE) of the training set is 1.29 years, and the Median Absolute Deviation (MAD) is 0.98 years. The Mean Absolute Error (MAE) of the validation set is 3.24 years, and the Median Absolute Deviation (MAD) is 2.3 years. Our method has higher accuracy in age prediction in comparison with other methylation-based age prediction methods.
    Keywords:  CpG sites; DNA methylation; age prediction; deep learning
    DOI:  https://doi.org/10.3390/bioengineering11010034
  2. Front Physiol. 2023 ;14 1279548
    Mitochondrial-related microRNAs and their roles in cellular senescence.
    Ling Luo, Xingna An, Yinghui Xiao, Xiguang Sun, Sijie Li, Yingzhao Wang, Weixia Sun, Dehai Yu.
      Aging is a natural aspect of mammalian life. Although cellular mortality is inevitable, various diseases can hasten the aging process, resulting in abnormal or premature senescence. As cells age, they experience distinctive morphological and biochemical shifts, compromising their functions. Research has illuminated that cellular senescence coincides with significant alterations in the microRNA (miRNA) expression profile. Notably, a subset of aging-associated miRNAs, originally encoded by nuclear DNA, relocate to mitochondria, manifesting a mitochondria-specific presence. Additionally, mitochondria themselves house miRNAs encoded by mitochondrial DNA (mtDNA). These mitochondria-residing miRNAs, collectively referred to as mitochondrial miRNAs (mitomiRs), have been shown to influence mtDNA transcription and protein synthesis, thereby impacting mitochondrial functionality and cellular behavior. Recent studies suggest that mitomiRs serve as critical sensors for cellular senescence, exerting control over mitochondrial homeostasis and influencing metabolic reprogramming, redox equilibrium, apoptosis, mitophagy, and calcium homeostasis-all processes intimately connected to senescence. This review synthesizes current findings on mitomiRs, their mitochondrial targets, and functions, while also exploring their involvement in cellular aging. Our goal is to shed light on the potential molecular mechanisms by which mitomiRs contribute to the aging process.
    Keywords:  cellular senescence; epigenetics; mitochondria; mitomiRs; noncoding RNA
    DOI:  https://doi.org/10.3389/fphys.2023.1279548
  3. J Colloid Interface Sci. 2024 Jan 06. pii: S0021-9797(24)00038-9. [Epub ahead of print]660 534-544
    Rapamycin functionalized carbon Dots: Target-oriented synthesis and suppression of vascular cell senescence.
    Jiaxin Dong, Qi Wang, Tingting Gu, Guanxiong Liu, Yuri V Petrov, Vladimir E Baulin, Aslan Yu Tsivadze, Dechang Jia, Yu Zhou, Huiping Yuan, Baoqiang Li.
      Suppression of vascular cell senescence is of great significance in preventing cardiovascular diseases such as hypertension and atherosclerosis. The oxidative stress damage caused by reactive oxygen species (ROS) can lead to cellular senescence. Rapamycin (Rapa) is well known to suppress cell senescence via mammalian target of rapamycin (mTOR) pathway. However, poor water solubility and lack of ROS scavenging ability limit the further development of Rapa. To improve the solubility of Rapa and endow with ROS scavenging ability, Rapa functionalized carbon dots (Rapa-CDs) are target-oriented synthesized via free radical polymerization combination with hydrothermal carbonization. Rapa-CDs improve the solubility of Rapa and show ROS scavenging abilities. The solubility of Rapa-CDs with 9.41 g is improved 3.6 × 104 times higher than that of Rapa (2.6 × 10-4 g). The half maximal inhibitory concentration (IC50) of Rapa-CDs toward hydroxyl radical (•OH) and 2,2-Diphenyl-1-picrylhydrazyl free radical (DPPH•) are 0.18 and 0.17 mg/mL, respectively. Rapa-CDs show anti-oxidative stress effect in HEVECs (Human Umbilical Vein Endothelial Cells) via reducing ROS levels by 87 %. Rapa-CDs alleviate HUVECs senescence by suppressing mTOR overactivation, attenuate the expression of P53, P21 and P16. The study demonstrates the target-oriented synthesis of drugs functionalized CDs with anti-senescence via dual-pathway of anti-oxidative stress and mTOR.
    Keywords:  Carbon dots; Cell senescence; Chitosan; ROS; Rapamycin; Target-oriented synthesis
    DOI:  https://doi.org/10.1016/j.jcis.2024.01.032
  4. Ageing Res Rev. 2024 Jan 23. pii: S1568-1637(24)00022-9. [Epub ahead of print] 102204
    Epigenetic Reprogramming as a Key to Reverse Ageing and Increase Longevity.
    Beatriz Pereira, Francisca P Correia, Inês A Alves, Margarida Costa, Mariana Gameiro, Ana P Martins, Jorge A Saraiva.
      The pursuit for the fountain of youth has long been a fascination amongst scientists and humanity. Ageing is broadly characterized by a cellular decline with increased susceptibility to age-related diseases, being intimately associated with epigenetic modifications. Recently, reprogramming-induced rejuvenation strategies have begun to greatly alter longevity research not only to tackle age-related defects but also to possibly reverse the cellular ageing process. Hence, in this review, we highlight the major epigenetic changes during ageing and the state-of-art of the current emerging epigenetic reprogramming strategies leveraging on transcription factors. Notably, partial reprogramming enables the resetting of the ageing clock without erasing cellular identity. Promising chemical-based rejuvenation strategies harnessing small molecules, including DNA methyltransferase and histone deacetylase inhibitors are also discussed. Moreover, in parallel to longevity interventions, the foundations of epigenetic clocks for accurate ageing assessment and evaluation of reprogramming approaches are briefly presented. Going further, with such scientific breakthroughs, we are witnessing a rise in the longevity biotech industry aiming to extend the health span and ideally achieve human rejuvenation one day. In this context, we overview the main scenarios proposed for the future of the socio-economic and ethical challenges associated with such an emerging field. Ultimately, this review aims to inspire future research on interventions that promote healthy ageing for all.
    Keywords:  DNA methylation; epigenetic clock; epigenetic reprogramming; histones; longevity; small molecules
    DOI:  https://doi.org/10.1016/j.arr.2024.102204
  5. Foods. 2024 Jan 15. pii: 269. [Epub ahead of print]13(2):
    The Potential of Using Cochayuyo (Durvillaea incurvata) Extract Obtained by Ultrasound-Assisted Extraction to Fight against Aging-Related Diseases.
    Nicolás Muñoz-Molina, Javier Parada, Mario Simirgiotis, Romina Montecinos-González.
      The world's population is in a demographical transition, with an increase in the number of older adults and prevalence of diseases related to aging. This study evaluated in vitro the potential of using Durvillaea incurvata extract (extracted using ultrasound-assisted extraction) to inhibit key enzymes associated with the development of age-related diseases. Our results show that an extract extracted via ultrasound-assisted extracted, as well as an extract conventional extracted from Durvillaea incurvata, presented antidiabetes potential by exhibiting inhibitory activity against α-glucosidase (91.8 ± 1.0% and 93.8 ± 0.3%, respectively, at 500 µg/mL) and α-amylase (42.2 ± 1.4% and 61.9 ± 0.9%, respectively, at 1500 µg/mL) enzymes related to starch digestion and postprandial glycemic response. Also, the extracts showed inhibitory activity against the enzymes acetylcholinesterase (51.5% and 50.8%, respectively, at 500 µg/mL) and butyrylcholinesterase (32.8% and 34.4%, respectively, at 0.5 mg/mL), the biomarkers associated with Alzheimer's disease, and angiotensin-converting enzyme (98.7 ± 7.4% and 93.0 ± 3.4%, respectively, at 2.0 mg/mL), which is key in the regulation of vascular tone and blood pressure and helps to prevent the development of hypertension. In conclusion, the extract of Durvillaea incurvata obtained from ultrasound-assisted extraction has the potential to prevent the development of age-related pathologies such as diabetes, Alzheimer's disease, and hypertension.
    Keywords:  Alzheimer’s; Durvillaea incurvata; aging; diabetes; enzyme inhibition; hypertension
    DOI:  https://doi.org/10.3390/foods13020269
  6. Cardiovasc Hematol Agents Med Chem. 2024 Jan 23.
    Endothelial Cell Aging and Autophagy Dysregulation.
    Basheer Abdullah Marzoog.
      Entropy is a natural process that affects all living cells, including senescence, an irreversible physiological process that impairs cell homeostasis. Age is a significant factor in disease development, and the pathogenesis of endothelial cell aging is multifactorial. Autophagy dysfunction accelerates endothelial cell aging and cell death, while autophagy preserves endothelial cell youthfulness through intracellular homeostasis and gene expression regulation. Sirt, mTORC1, and AMPK are youthfulness genes that induce autophagy by inhibiting mTOR and upregulating FIP200/Atg13/ULK1. Aged endothelial cells have decreased levels of Lamin B1, γH2AX, Ki67, BrdU, PCNA, and SA β-Gal. Maintaining healthy young endothelial cells can prevent most cardiovascular diseases. Autophagy targeting is a potential future therapeutic strategy to modify endothelial cell age and potentially slow or reverse the aging process. This article provides state-of-the-art research on the role of autophagy in endothelial cell aging. Hypothesizing that autophagy dysregulation is associated with early endothelial cell dysfunction and further clinical sequelae, including atherosclerosis formation, leading to various cardiovascular diseases.
    Keywords:  Aging; Autophagy; Longevity; Pathogenesis; Senolytics; Sirtuin; endothelial cell
    DOI:  https://doi.org/10.2174/0118715257275690231129101408
  7. J Biomed Sci. 2024 Jan 23. 31(1): 15
    Hesperetin activates CISD2 to attenuate senescence in human keratinocytes from an older person and rejuvenates naturally aged skin in mice.
    Zhao-Qing Shen, Cheng-Yen Chang, Chi-Hsiao Yeh, Chung-Kuang Lu, Hao-Chih Hung, Tai-Wen Wang, Kuan-Sheng Wu, Chien-Yi Tung, Ting-Fen Tsai.
       BACKGROUND: CDGSH iron-sulfur domain-containing protein 2 (CISD2), a pro-longevity gene, mediates healthspan in mammals. CISD2 is down-regulated during aging. Furthermore, a persistently high level of CISD2 promotes longevity and ameliorates an age-related skin phenotype in transgenic mice. Here we translate the genetic evidence into a pharmaceutical application using a potent CISD2 activator, hesperetin, which enhances CISD2 expression in HEK001 human keratinocytes from an older person. We also treated naturally aged mice in order to study the activator's anti-aging efficacy.
    METHODS: We studied the biological effects of hesperetin on aging skin using, firstly, a cell-based platform, namely a HEK001 human keratinocyte cell line established from an older person. Secondly, we used a mouse model, namely old mice at 21-month old. In the latter case, we investigate the anti-aging efficacy of hesperetin on ultraviolet B (UVB)-induced photoaging and naturally aged skin. Furthermore, to identify the underlying mechanisms and potential biological pathways involved in this process we carried out transcriptomic analysis. Finally, CISD2 knockdown HEK001 keratinocytes and Cisd2 knockout mice were used to study the Cisd2-dependent effects of hesperetin on skin aging.
    RESULTS: Four findings are pinpointed. Firstly, in human skin, CISD2 is mainly expressed in proliferating keratinocytes from the epidermal basal layer and, furthermore, CISD2 is down-regulated in the sun-exposed epidermis. Secondly, in HEK001 human keratinocytes from an older person, hesperetin enhances mitochondrial function and protects against reactive oxygen species-induced oxidative stress via increased CISD2 expression; this enhancement is CISD2-dependent. Additionally, hesperetin alleviates UVB-induced damage and suppresses matrix metalloproteinase-1 expression, the latter being a major indicator of UVB-induced damage in keratinocytes. Thirdly, transcriptomic analysis revealed that hesperetin modulates a panel of differentially expressed genes that are associated with mitochondrial function, redox homeostasis, keratinocyte function, and inflammation in order to attenuate senescence. Intriguingly, hesperetin activates two known longevity-associated regulators, namely FOXO3a and FOXM1, in order to suppress the senescence-associated secretory phenotype. Finally, in mouse skin, hesperetin enhances CISD2 expression to ameliorate UVB-induced photoaging and this occurs via a mechanism involving CISD2. Most strikingly, late-life treatment with hesperetin started at 21-month old and lasting for 5 months, is able to retard skin aging and rejuvenate naturally aged skin in mice.
    CONCLUSIONS: Our results reveal that a pharmacological elevation of CISD2 expression at a late-life stage using hesperetin treatment is a feasible approach to effectively mitigating both intrinsic and extrinsic skin aging and that hesperetin could act as a functional food or as a skincare product for fighting skin aging.
    Keywords:  CISD2; CISD2 activator; Cellular senescence; Hesperetin; Keratinocytes; Mitochondrial function; Skin aging; Skin rejuvenation
    DOI:  https://doi.org/10.1186/s12929-024-01005-w
  8. Chem Biol Interact. 2024 Jan 24. pii: S0009-2797(24)00036-X. [Epub ahead of print] 110890
    Fisetin suppresses chondrocyte senescence and attenuates osteoarthritis progression by targeting sirtuin 6.
    Xuezhong Wang, Xuyang Li, Jianlin Zhou, Zheng Lei, Xiaoming Yang.
      Osteoarthritis (OA) is the most common type of arthritis and is an age-related joint disease that is particularly prevalent in subjects over 65 years old. The chronic rise of senescent cells has a close correlation with age-related diseases such as OA, and the senescence-associated secretory phenotype (SASP) is implicated in OA cartilage degeneration pathogenesis. Sirtuin 6 (SIRT6) is likely to be a key senescence-related regulator. Fisetin (FST) is a natural flavonol of the flavonoid family that is recommended as a senolytic drug to extend health and lifespan. However, the potential chondroprotective effects of FST on OA rats are largely unclarified. The aim of this study is to investigate the ameliorative effects of FST on OA joint cartilage and the relationship with SIRT6 and the detailed mechanisms from anti-inflammatory and anti-senescent perspectives. Rats were subjected to destabilization of the medial meniscus (DMM) surgery as a means of inducing the experimental OA model in vivo. Chondrocytes treated with IL-1β were utilized for mimicking the OA cell model in vitro. Intra-articular injection of FST, OSS_128,167 (OSS, SIRT6 inhibitor), and MDL800 (MDL, SIRT6 agonist) in vivo or administering them in IL-1β-induced rat chondrocytes in vitro were performed in order to determine the effects FST has on OA and the link with SIRT6. This study found SIRT6 level to be negatively correlated with OA severity. SIRT6 downregulation was validated in the joint cartilages of DMM rats and IL-1β-treated chondrocytes. It was also notably demonstrated that FST can activate SIRT6. Both the administration of FST and activation of SIRT6 using MDL were found to rescue cartilage erosion, decrease extracellular matrix (ECM) degradation, prevent cartilage from apoptosis, and improve detrimental senescence-related phenotype. The alleviative effects of FST against inflammation, ECM degradation, apoptosis, and senescence in IL-1β-stimulated chondrocytes were also confirmed. SIRT6 loss occurs in articular cartilage in OA pathogenesis, which is linked to aging. FST attenuates injury-induced aging-related phenotype changes in chondrocytes through the targeting of SIRT6.
    Keywords:  Anti-Senescent; Cartilage; Fisetin; Osteoarthritis; Sirtuin 6
    DOI:  https://doi.org/10.1016/j.cbi.2024.110890
  9. Genes (Basel). 2023 Dec 21. pii: 16. [Epub ahead of print]15(1):
    Biological Aging Acceleration Due to Environmental Exposures: An Exciting New Direction in Toxicogenomics Research.
    Sudipta Dutta, Jaclyn M Goodrich, Dana C Dolinoy, Douglas M Ruden.
      Biological clock technologies are designed to assess the acceleration of biological age (B-age) in diverse cell types, offering a distinctive opportunity in toxicogenomic research to explore the impact of environmental stressors, social challenges, and unhealthy lifestyles on health impairment. These clocks also play a role in identifying factors that can hinder aging and promote a healthy lifestyle. Over the past decade, researchers in epigenetics have developed testing methods that predict the chronological and biological age of organisms. These methods rely on assessing DNA methylation (DNAm) levels at specific CpG sites, RNA levels, and various biomolecules across multiple cell types, tissues, and entire organisms. Commonly known as 'biological clocks' (B-clocks), these estimators hold promise for gaining deeper insights into the pathways contributing to the development of age-related disorders. They also provide a foundation for devising biomedical or social interventions to prevent, reverse, or mitigate these disorders. This review article provides a concise overview of various epigenetic clocks and explores their susceptibility to environmental stressors.
    Keywords:  DNA methylation; biological clocks; epigenetic clocks; toxicogenomics; toxicology
    DOI:  https://doi.org/10.3390/genes15010016
  10. Biomedicines. 2023 Dec 20. pii: 16. [Epub ahead of print]12(1):
    The Dynamic SUMOylation Changes and Their Potential Role in the Senescence of APOE4 Mice.
    Yangqi Xu, Wenwen Cai, Shaoming Sang, Xiaoqin Cheng, Boru Jin, Xiangteng Zhao, Chunjiu Zhong.
      The ε4 allele of apolipoprotein E (APOE4) and aging are the major risk factors for Alzheimer's disease (AD). SUMOylation is intimately linked to the development of AD and the aging process. However, the SUMOylation status in APOE4 mice has not been uncovered. In this study, we investigated SENP1 and SUMOylation changes in the brains of aged APOE3 and APOE4 mice, aiming to understand their potential impact on mitochondrial metabolism and their contribution to cellular senescence in APOE4 mice. Concurrently, SUMO1-conjugated protein levels decreased, while SUMO2/3-conjugated protein levels increased relatively with the aging of APOE4 mice. This suggests that the equilibrium between the SUMOylation and deSUMOylation processes may be associated with senescence and longevity. Our findings highlight the significant roles of SENP1 and SUMOylation changes in APOE4-driven pathology and the aging process.
    Keywords:  APOE4; Alzheimer’s disease; SENP; SUMOylation; aging
    DOI:  https://doi.org/10.3390/biomedicines12010016
  11. Cells. 2024 Jan 09. pii: 119. [Epub ahead of print]13(2):
    The Impact of Long Noncoding RNAs in Tissue Regeneration and Senescence.
    Júlia Tavares E Silva, João Pessoa, Sandrina Nóbrega-Pereira, Bruno Bernardes de Jesus.
      Overcoming senescence with tissue engineering has a promising impact on multiple diseases. Here, we provide an overview of recent studies in which cellular senescence was inhibited through the up/downregulation of specific lncRNAs. This approach prevented senescence in the bones, joints, nervous system, heart, and blood vessels, with a potential impact on regeneration and the prevention of osteoarthritis and osteoporosis, as well as neurodegenerative and cardiovascular diseases. Senescence of the skin and liver could also be prevented through the regulation of cellular levels of specific lncRNAs, resulting in the rejuvenation of cells from these organs and their potential protection from disease. From these exciting achievements, which support tissue regeneration and are not restricted to stem cells, we propose lncRNA regulation through RNA or gene therapies as a prospective preventive and therapeutic approach against aging and multiple aging-related diseases.
    Keywords:  aging; cardiovascular disease; cellular senescence; downregulation; long noncoding RNAs; neurodegeneration; upregulation
    DOI:  https://doi.org/10.3390/cells13020119
  12. Immunity. 2024 Jan 17. pii: S1074-7613(24)00026-8. [Epub ahead of print]
    Type 2 cytokine signaling in macrophages protects from cellular senescence and organismal aging.
    Zhao Zhou, Jingfei Yao, Dongmei Wu, Xun Huang, Yushuang Wang, Xinmeng Li, Qiang Lu, Yifu Qiu.
      Accumulation of senescent cells in organs and tissues is a hallmark of aging and known to contribute to age-related diseases. Although aging-associated immune dysfunction, or immunosenescence, is known to contribute to this process, the underlying mechanism remains elusive. Here, we report that type 2 cytokine signaling deficiency accelerated aging and, conversely, that the interleukin-4 (IL-4)-STAT6 pathway protected macrophages from senescence. Mechanistically, activated STAT6 promoted the expression of genes involved in DNA repair both via homologous recombination and Fanconi anemia pathways. Conversely, STAT6 deficiency induced release of nuclear DNA into the cytoplasm to promote tissue inflammation and organismal aging. Importantly, we demonstrate that IL-4 treatment prevented macrophage senescence and improved the health span of aged mice to an extent comparable to senolytic treatment, with further additive effects when combined. Together, our findings support that type 2 cytokine signaling protects macrophages from immunosenescence and thus hold therapeutic potential for improving healthy aging.
    Keywords:  DNA repair; IL-4; STAT6; aging; immunosenescence; inflammaging; macrophage; type 2 cytokine
    DOI:  https://doi.org/10.1016/j.immuni.2024.01.001
  13. Alcohol Clin Exp Res (Hoboken). 2024 Jan 26.
    Biological aging markers in blood and brain tissue indicate age acceleration in alcohol use disorder.
    Lea Zillich, Metin Cetin, Elisabeth M Hummel, Eric Poisel, Gabriel R Fries, Josef Frank, Fabian Streit, Jerome C Foo, Lea Sirignano, Marion M Friske, Bernd Lenz, Sabine Hoffmann, Kristina Adorjan, Falk Kiefer, Georgy Bakalkin, Anita C Hansson, Falk W Lohoff, Olli Kärkkäinen, Eloise Kok, Pekka J Karhunen, Greg T Sutherland, Consuelo Walss-Bass, Rainer Spanagel, Marcella Rietschel, Dirk A Moser, Stephanie H Witt.
       BACKGROUND: Alcohol use disorder (AUD) is associated with increased mortality and morbidity risk. A reason for this could be accelerated biological aging, which is strongly influenced by disease processes such as inflammation. As recent studies of AUD show changes in DNA methylation and gene expression in neuroinflammation-related pathways in the brain, biological aging represents a potentially important construct for understanding the adverse effects of substance use disorders. Epigenetic clocks have shown accelerated aging in blood samples from individuals with AUD. However, no systematic evaluation of biological age measures in AUD across different tissues and brain regions has been undertaken.
    METHODS: As markers of biological aging (BioAge markers), we assessed Levine's and Horvath's epigenetic clocks, DNA methylation telomere length (DNAmTL), telomere length (TL), and mitochondrial DNA copy number (mtDNAcn) in postmortem brain samples from Brodmann Area 9 (BA9), caudate nucleus, and ventral striatum (N = 63-94), and in whole blood samples (N = 179) of individuals with and without AUD. To evaluate the association between AUD status and BioAge markers, we performed linear regression analyses while adjusting for covariates.
    RESULTS: The majority of BioAge markers were significantly associated with chronological age in all samples. Levine's epigenetic clock and DNAmTL were indicative of accelerated biological aging in AUD in BA9 and whole blood samples, while Horvath's showed the opposite effect in BA9. No significant association of AUD with TL and mtDNAcn was detected. Measured TL and DNAmTL showed only small correlations in blood and none in brain.
    CONCLUSIONS: The present study is the first to simultaneously investigate epigenetic clocks, telomere length, and mtDNAcn in postmortem brain and whole blood samples in individuals with AUD. We found evidence for accelerated biological aging in AUD in blood and brain, as measured by Levine's epigenetic clock, and DNAmTL. Additional studies of different tissues from the same individuals are needed to draw valid conclusions about the congruence of biological aging in blood and brain.
    Keywords:  alcohol use disorder; biological aging; copy numbers of mitochondrial DNA; epigenetic clocks; telomere length
    DOI:  https://doi.org/10.1111/acer.15241
  14. Front Aging. 2023 ;4 1258183
    Development of an epigenetic clock to predict visual age progression of human skin.
    Agata Bienkowska, Günter Raddatz, Jörn Söhle, Boris Kristof, Henry Völzke, Stefan Gallinat, Frank Lyko, Lars Kaderali, Marc Winnefeld, Elke Grönniger, Cassandra Falckenhayn.
      Aging is a complex process characterized by the gradual decline of physiological functions, leading to increased vulnerability to age-related diseases and reduced quality of life. Alterations in DNA methylation (DNAm) patterns have emerged as a fundamental characteristic of aged human skin, closely linked to the development of the well-known skin aging phenotype. These changes have been correlated with dysregulated gene expression and impaired tissue functionality. In particular, the skin, with its visible manifestations of aging, provides a unique model to study the aging process. Despite the importance of epigenetic age clocks in estimating biological age based on the correlation between methylation patterns and chronological age, a second-generation epigenetic age clock, which correlates DNAm patterns with a particular phenotype, specifically tailored to skin tissue is still lacking. In light of this gap, we aimed to develop a novel second-generation epigenetic age clock explicitly designed for skin tissue to facilitate a deeper understanding of the factors contributing to individual variations in age progression. To achieve this, we used methylation patterns from more than 370 female volunteers and developed the first skin-specific second-generation epigenetic age clock that accurately predicts the skin aging phenotype represented by wrinkle grade, visual facial age, and visual age progression, respectively. We then validated the performance of our clocks on independent datasets and demonstrated their broad applicability. In addition, we integrated gene expression and methylation data from independent studies to identify potential pathways contributing to skin age progression. Our results demonstrate that our epigenetic age clock, VisAgeX, specifically predicting visual age progression, not only captures known biological pathways associated with skin aging, but also adds novel pathways associated with skin aging.
    Keywords:  DNA methylation; age progression; aging; biological age; epigenetic age clock; skin aging; visual age; wrinkles
    DOI:  https://doi.org/10.3389/fragi.2023.1258183
  15. Biology (Basel). 2024 Jan 08. pii: 36. [Epub ahead of print]13(1):
    Red Ginseng Attenuates the Hepatic Cellular Senescence in Aged Mice.
    Da-Yeon Lee, Juliana Arndt, Jennifer F O'Connell, Josephine M Egan, Yoo Kim.
      Cellular senescence is defined as an irreversible cell cycle arrest accompanied by morphological and physiological alterations during aging. Red ginseng (RG), processed from fresh ginseng (Panax ginseng C.A. Meyer) with a one-time steaming and drying process, is a well-known beneficial herbal medicine showing antioxidant, anti-inflammatory, and anti-aging properties. The current study aimed to investigate the benefits of RG in alleviating hepatic cellular senescence and its adverse effects in 19-month-old aged mice. We applied two different intervention methods and durations to compare RG's effects in a time-dependent manner: (1) oral gavage injection for 4 weeks and (2) ad libitum intervention for 14 weeks. We observed that 4-week RG administration was exerted to maintain insulin homeostasis against developing age-associated insulin insensitivity and suppressed cellular senescence pathway in the liver and primary hepatocytes. Moreover, with remarkable improvement of insulin homeostasis, 14-week RG supplementation downregulated the activation of c-Jun N-terminal kinase (JNK) and its downstream transcriptional factor nuclear factor-κB (NF-κB) in aged mice. Lastly, RG treatment significantly reduced the senescence-associated β-galactosidase (SA-β-gal)-positive cells in primary hepatocytes and ionizing radiation (IR)-exposed mouse embryonic fibroblasts (MEFs). Taken together, we suggest that RG can be a promising candidate for a senolytic substance by preventing hepatic cellular senescence.
    Keywords:  apoptosis; cellular senescence; inflammation; insulin homeostasis; liver; red ginseng
    DOI:  https://doi.org/10.3390/biology13010036
  16. bioRxiv. 2024 Jan 09. pii: 2024.01.08.574768. [Epub ahead of print]
    Primary oocytes with cellular senescence features are involved in ovarian aging in mice.
    Hao Yan, Edgar Andres Diaz Miranda, Shiying Jin, Faith Wilson, Kang An, Brooke Godbee, Xiaobin Zheng, Astrid Roshealy Brau-Rodríguez, Lei Lei.
      In mammalian females, quiescent primordial follicles serve as the ovarian reserve and sustain normal ovarian function and egg production via folliculogenesis. The loss of primordial follicles causes ovarian aging. Cellular senescence, characterized by cell cycle arrest and production of the senescence-associated secretory phenotype (SASP), is associated with tissue aging. In the present study, we report that some quiescent primary oocytes in primordial follicles become senescent in adult mouse ovaries. The senescent primary oocytes share senescence markers characterized in senescent somatic cells. The senescent primary oocytes were observed in young adult mouse ovaries, remained at approximately 15% of the total primary oocytes during ovarian aging from 6 months to 12 months, and accumulated in aged ovaries. Administration of a senolytic drug ABT263 to 3-month-old mice reduced the percentage of senescent primary oocytes and the transcription of the SASP cytokines in the ovary. In addition, led to increased numbers of primordial and total follicles and a higher rate of oocyte maturation and female fertility. Our study provides experimental evidence that primary oocytes, a germline cell type that is arrested in meiosis, become senescent in adult mouse ovaries and that senescent cell clearance reduced primordial follicle loss and mitigated ovarian aging phenotypes.
    DOI:  https://doi.org/10.1101/2024.01.08.574768
  17. Trends Pharmacol Sci. 2024 Jan 19. pii: S0165-6147(24)00002-6. [Epub ahead of print]
    Revisiting sensitivity of senescent cells to BH3 mimetics.
    Nadine Martin, Anda Huna, Athanasios Tsalikis, David Bernard.
      B cell leukemia/lymphoma 2 (BCL2) homology domain 3 (BH3) mimetics were reported to selectively kill senescent cells and improve age-related diseases. Defining why these cells show increased sensitivity to these molecules will help to identify new pharmacological compounds with senolytic activity. Here, we discuss how recent research findings provide new clues to understand this vulnerability.
    Keywords:  BCL2; MOMP; aging; cellular senescence; senolytics
    DOI:  https://doi.org/10.1016/j.tips.2024.01.002
  18. Antioxidants (Basel). 2024 Jan 16. pii: 109. [Epub ahead of print]13(1):
    Vutiglabridin Alleviates Cellular Senescence with Metabolic Regulation and Circadian Clock in Human Dermal Fibroblasts.
    Jin-Woong Heo, Hye-Eun Lee, Jimin Lee, Leo Sungwong Choi, Jaejin Shin, Ji-Young Mun, Hyung-Soon Park, Sang-Chul Park, Chang-Hoon Nam.
      The process of cellular senescence, which is characterized by stable cell cycle arrest, is strongly associated with dysfunctional cellular metabolism and circadian rhythmicity, both of which are reported to result from and also be causal to cellular senescence. As a result, modifying any of them-senescence, metabolism, or the circadian clock-may affect all three simultaneously. Obesity accelerates aging by disrupting the homeostasis of reactive oxygen species (ROS) via an increased mitochondrial burden of fatty acid oxidation. As a result, if senescence, metabolism, and circadian rhythm are all linked, anti-obesity treatments may improve metabolic regulation while also alleviating senescence and circadian rhythm. Vutiglabridin is a small molecule in clinical trials that improves obesity by enhancing mitochondrial function. We found that chronic treatment of senescent primary human dermal fibroblasts (HDFs) with vutiglabridin alleviates all investigated markers of cellular senescence (SA-β-gal, CDKN1A, CDKN2A) and dysfunctional cellular circadian rhythm (BMAL1) while remarkably preventing the alterations of mitochondrial function and structure that occur during the process of cellular senescence. Our results demonstrate the significant senescence-alleviating effects of vutiglabridin, specifically with the restoration of cellular circadian rhythmicity and metabolic regulation. These data support the potential development of vutiglabridin against aging-associated diseases and corroborate the intricate link between cellular senescence, metabolism, and the circadian clock.
    Keywords:  cellular senescence; circadian clocks; human dermal fibroblasts; metabolism; mitochondrial homeostasis
    DOI:  https://doi.org/10.3390/antiox13010109
  19. Res Sq. 2024 Jan 05. pii: rs.3.rs-3617723. [Epub ahead of print]
    Humanization of the mouse telomerase gene reset telomeres to human length.
    Jiyue Zhu, De Cheng, Fan Zhang, Kenneth Porter, Shuwen Wang, Hui Zhang, Christopher Davis, Gavin Robertson.
      Telomeres undergo shortening with each cell division, serving as biomarkers of human aging, which is characterized by short telomeres and restricted telomerase expression in adult tissues. Contrarily, mice, featuring their longer telomeres and widespread telomerase activity, present limitations as models for understanding telomere-related human biology and diseases. To bridge this gap, we engineered a mouse strain with a humanized mTert gene, hmTert , wherein specific non-coding sequences were replaced with their human counterparts. The hmTert gene, encoding the wildtype mTert protein, was repressed in adult tissues beyond the gonads and thymus, closely resembling the regulatory pattern of the human TERT gene. Remarkably, the hmTert gene rescued telomere dysfunction in late generations of mTert -knockout mice. Through successive intercrosses of Tert h/- mice, telomere length progressively declined, stabilizing below 10-kb. Tert h/h mice achieved a human-like average telomere length of 10-12 kb, contrasting with the 50-kb length in wildtype C57BL/6J mice. Despite shortened telomeres, Tert h/h mice maintained normal body weight and cell homeostasis in highly proliferative tissues. Notably, colonocyte proliferation decreased significantly in Terth/h mice during dextran sodium sulfate-induced ulcerative colitis-like pathology, suggesting limitations on cellular renewal due to short telomeres. Our findings underscore the genetic determination of telomere homeostasis in mice by the Tert gene. These mice, exhibiting humanized telomere homeostasis, serve as a valuable model for exploring fundamental questions related to human aging and cancer.
    DOI:  https://doi.org/10.21203/rs.3.rs-3617723/v1
  20. Environ Int. 2024 Jan 17. pii: S0160-4120(24)00033-3. [Epub ahead of print]184 108447
    The mixed effect of Endocrine-Disrupting chemicals on biological age Acceleration: Unveiling the mechanism and potential intervention target.
    Weichao Huang, Zilong Zhang, Manuel Colucci, Linghui Deng, Mi Yang, Xinyi Huang, Xianghong Zhou, Yumin Jin, Edoardo Lazzarini, Carolina Balbi, Juanola Juarez Oriol, Aurora Valdata, Silvia Bressan, Yu Zhan, Fang Qi, Qiang Wei, Lu Yang, Xiaoli Zou, Shi Qiu.
       INTRODUCTION: Although previous studies investigated the potential adverse effects of endocrine-disrupting chemicals (EDCs) on biological age acceleration and aging-related diseases, the mixed effect of multiple types of EDCs on biological age acceleration, including its potential underlying mechanism, remains unclear.
    METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) were used to analyze biological age measures, including Klemera-Doubal method biological age (KDM-BA), phenotypic age, and homeostatic dysregulation (HD). Weight quantile sum (WQS) regression was performed to screen biological age-related EDCs (BA-EDCs) and assess the mixed effect of BA-EDCs on biological age acceleration and aging-related disease. Targets of BA-EDCs were obtained from three databases, while heart aging-related genes were obtained from the Aging Anno database. Protein-protein interaction (PPI) network and MCODE algorithm were applied to identify potential interactions between BA-EDC targets and heart aging-related genes. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed to identify related pathways.
    RESULTS: This cross-sectional study included 1,439 participants. A decile increase in BA-EDCs co-exposure was associated with 0.31 years and 0.17 years of KDM-BA and phenotypic age acceleration, respectively. The mixed effect of BA-EDCs was associated with an increased prevalence of atherosclerotic cardiovascular disease (ASCVD). Vitamins C and E demonstrated a significant interaction effect on the association between BA-EDCs and KDM-BA acceleration. PPI network and functional enrichment analysis indicated that the AGE-RAGE signaling pathway in diabetic complications was significantly enriched.
    CONCLUSION: Our results showed that the co-exposure effect of BA-EDCs was associated with biological age acceleration and ASCVD, with the AGE-RAGE signaling pathway being the underlying mechanism. Vitamins C and E may also be an actionable target for preventing EDC-induced biological aging.
    Keywords:  AGE-RAGE signaling pathway; Biological age; Endocrine-disrupting chemical; Paraben; Phthalate
    DOI:  https://doi.org/10.1016/j.envint.2024.108447
  21. Nat Aging. 2024 Jan 24.
    TXNRD1 drives the innate immune response in senescent cells with implications for age-associated inflammation.
    Xue Hao, Bo Zhao, Martina Towers, Liping Liao, Edgar Luzete Monteiro, Xin Xu, Christina Freeman, Hongzhuang Peng, Hsin-Yao Tang, Aaron Havas, Andrew V Kossenkov, Shelley L Berger, Peter D Adams, David W Speicher, David Schultz, Ronen Marmorstein, Kenneth S Zaret, Rugang Zhang.
      Sterile inflammation, also known as 'inflammaging', is a hallmark of tissue aging. Cellular senescence contributes to tissue aging, in part, through the secretion of proinflammatory factors collectively known as the senescence-associated secretory phenotype (SASP). The genetic variability of thioredoxin reductase 1 (TXNRD1) is associated with aging and age-associated phenotypes such as late-life survival, activity of daily living and physical performance in old age. TXNRD1's role in regulating tissue aging has been attributed to its enzymatic role in cellular redox regulation. Here, we show that TXNRD1 drives the SASP and inflammaging through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) innate immune response pathway independently of its enzymatic activity. TXNRD1 localizes to cytoplasmic chromatin fragments and interacts with cGAS in a senescence-status-dependent manner, which is necessary for the SASP. TXNRD1 enhances the enzymatic activity of cGAS. TXNRD1 is required for both the tumor-promoting and immune surveillance functions of senescent cells, which are mediated by the SASP in vivo in mouse models. Treatment of aged mice with a TXNRD1 inhibitor that disrupts its interaction with cGAS, but not with an inhibitor of its enzymatic activity alone, downregulated markers of inflammaging in several tissues. In summary, our results show that TXNRD1 promotes the SASP through the innate immune response, with implications for inflammaging. This suggests that the TXNRD1-cGAS interaction is a relevant target for selectively suppressing inflammaging.
    DOI:  https://doi.org/10.1038/s43587-023-00564-1
  22. Curr Med Chem. 2024 Jan 12.
    The Possible Roles of β-alanine and L-carnosine in Anti-aging.
    Amin Gasmi, Pavan Kumar Mujawdiya, Roman Lysiuk, Mariia Shanaida, Massimiliano Peana, Salva Piscopo, Nataliya Beley, Svitlana Dzyha, Kateryna Smetanina, Volodymyr Shanaida, Stéphane Résimont, Geir Bjørklund.
      alanine (BA), being a non-proteinogenic amino acid, is an important constituent of L-carnosine (LC), which is necessary for maintaining the muscle buffering capacity and preventing a loss of muscle mass associated with aging effects. BA is also very important for normal human metabolism due to the formation of a part of pantothenate, which is incorporated into coenzyme A. BA is synthesized in the liver, and its combination with histidine results in the formation of LC, which accumulates in the muscles and brain tissues and has a well-defined physiological role as a good buffer for the pH range of muscles that caused its rapidly increased popularity as ergogenic support to sports performance. The main antioxidant mechanisms of LC include reactive oxygen species (ROS) scavenging and chelation of metal ions. With age, the buffering capacity of muscles also declines due to reduced concentration of LC and sarcopenia. Moreover, LC acts as an antiglycation agent, ultimately reducing the development of degenerative diseases. LC has an anti-inflammatory effect in autoimmune diseases such as osteoarthritis. As histidine is always present in the human body in higher concentrations than BA, humans have to get BA from dietary sources to support the required amount of this critical constituent to supply the necessary amount of LC synthesis. Also, BA has other beneficial effects, such as preventing skin aging and intestinal damage, improving the stress-- fighting capability of the muscle cells, and managing an age-related decline in memory and learning. In this review, the results of a detailed analysis of the role and various beneficial properties of BA and LC from the anti-aging perspective.
    Keywords:  L-carnosine; amino acid; anti-aging effect; beta-alanine; dietary supplements; dipeptide; dosages; sources
    DOI:  https://doi.org/10.2174/0109298673263561231117054447
  23. Biomedicines. 2024 Jan 03. pii: 98. [Epub ahead of print]12(1):
    Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Rescue Testicular Aging.
    Peng Luo, Xuren Chen, Feng Gao, Andy Peng Xiang, Chunhua Deng, Kai Xia, Yong Gao.
       BACKGROUND: Testicular aging is associated with diminished fertility and certain age-related ailments, and effective therapeutic interventions remain elusive. Here, we probed the therapeutic efficacy of exosomes derived from human umbilical cord mesenchymal stem cells (hUMSC-Exos) in counteracting testicular aging.
    METHODS: We employed a model of 22-month-old mice and administered intratesticular injections of hUMSC-Exos. Comprehensive analyses encompassing immunohistological, transcriptomic, and physiological assessments were conducted to evaluate the effects on testicular aging. Concurrently, we monitored alterations in macrophage polarization and the oxidative stress landscape within the testes. Finally, we performed bioinformatic analysis for miRNAs in hUMSC-Exos.
    RESULTS: Our data reveal that hUMSC-Exos administration leads to a marked reduction in aging-associated markers and cellular apoptosis while promoting cellular proliferation in aged testis. Importantly, hUMSC-Exos facilitated the restoration of spermatogenesis and elevated testosterone synthesis in aged mice. Furthermore, hUMSC-Exos could attenuate inflammation by driving the phenotypic shift of macrophages from M1 to M2 and suppress oxidative stress by reduced ROS production. Mechanistically, these efficacies against testicular aging may be mediated by hUMSC-Exos miRNAs.
    CONCLUSIONS: Our findings suggest that hUMSC-Exos therapy presents a viable strategy to ameliorate testicular aging, underscoring its potential therapeutic significance in managing testicular aging.
    Keywords:  exosome; macrophage; mesenchymal stem cell; spermatogenesis; testicular aging; testosterone
    DOI:  https://doi.org/10.3390/biomedicines12010098
  24. Nat Aging. 2024 Jan 24.
    Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction.
    Corina Amor, Inés Fernández-Maestre, Saria Chowdhury, Yu-Jui Ho, Sandeep Nadella, Courtenay Graham, Sebastian E Carrasco, Emmanuella Nnuji-John, Judith Feucht, Clemens Hinterleitner, Valentin J A Barthet, Jacob A Boyer, Riccardo Mezzadra, Matthew G Wereski, David A Tuveson, Ross L Levine, Lee W Jones, Michel Sadelain, Scott W Lowe.
      Senescent cells, which accumulate in organisms over time, contribute to age-related tissue decline. Genetic ablation of senescent cells can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness. While small-molecule drugs that eliminate senescent cells ('senolytics') partially replicate these phenotypes, they require continuous administration. We have developed a senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting the senescence-associated protein urokinase plasminogen activator receptor (uPAR), and we previously showed these can safely eliminate senescent cells in young animals. We now show that uPAR-positive senescent cells accumulate during aging and that they can be safely targeted with senolytic CAR T cells. Treatment with anti-uPAR CAR T cells improves exercise capacity in physiological aging, and it ameliorates metabolic dysfunction (for example, improving glucose tolerance) in aged mice and in mice on a high-fat diet. Importantly, a single administration of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.
    DOI:  https://doi.org/10.1038/s43587-023-00560-5
  25. Int J Gen Med. 2024 ;17 205-224
    Screening of Biomarkers Associated with Osteoarthritis Aging Genes and Immune Correlation Studies.
    Lanwei Xu, Zheng Wang, Gang Wang.
       Purpose: Osteoarthritis (OA) is a joint disease with a long and slow course, which is one of the major causes of disability in middle and old-aged people. This study was dedicated to excavating the cellular senescence-associated biomarkers of OA.
    Methods: The Gene Expression Omnibus (GEO) database was searched and five datasets pertaining to OA were obtained. After removing the batch effect, the GSE55235, GSE55457, GSE82107, and GSE12021 datasets were integrated together for screening of the candidate genes by differential analysis and weighted gene co-expression network analysis (WGCNA). Next, those genes were further filtered by machine learning algorithms to obtain cellular senescence-associated biomarkers of OA. Subsequently, enrichment analyses based on those biomarkers were conducted, and we profiled the infiltration levels of 22 types immune cells with the ERSORT algorithm. A lncRNA-miRNA-mRNA regulatory and drug-gene network were constructed. Finally, we validated the senescence-associated biomarkers at both in vivo and in vitro levels.
    Results: Five genes (BCL6, MCL1, SLC16A7, PIM1, and EPHA3) were authenticated as cellular senescence-associated biomarkers in OA. ROC curves demonstrated the reliable capacity of the five genes as a whole to discriminate OA samples from normal samples. The nomogram diagnostic model based on 5 genes proved to be a reliable predictor of OA. Single-gene GSEA results pointed to the involvement of the five biomarkers in immune-related pathways and oxidative phosphorylation in the development of OA. Immune infiltration analysis manifested that the five genes were significantly correlated with differential immune cells. Subsequently, a lncRNA-miRNA-mRNA network and gene-drug network containing were generated based on five cellular senescence-associated biomarkers in OA.
    Conclusion: A foundation for understanding the pathophysiology of OA and new insights into OA diagnosis and treatment were provided by the identification of five genes, namely BCL6, MCL1, SLC16A7, PIM1, and EPHA3, as biomarkers associated with cellular senescence in OA.
    Keywords:  PIM1; biomarkers; cellular senescence-related genes; drugs; osteoarthritis
    DOI:  https://doi.org/10.2147/IJGM.S447035
  26. Biol Direct. 2024 Jan 23. 19(1): 8
    PICLS with human cells is the first high throughput screening method for identifying novel compounds that extend lifespan.
    Mohammad Alfatah, Yizhong Zhang, Arshia Naaz, Trishia Yi Ning Cheng, Frank Eisenhaber.
      Gerontology research on anti-aging interventions with drugs could be an answer to age-related diseases, aiming at closing the gap between lifespan and healthspan. Here, we present two methods for assaying chronological lifespan in human cells: (1) a version of the classical outgrowth assay with quantitative assessment of surviving cells and (2) a version of the PICLS method (propidium iodide fluorescent-based measurement of cell death). Both methods are fast, simple to conduct, cost-effective, produce quantitative data for further analysis and can be used with diverse human cell lines. Whereas the first method is ideal for validation and testing the post-intervention reproductive potential of surviving cells, the second method has true high-throughput screening potential. The new technologies were validated with known anti-aging compounds (2,5-anhydro-D-mannitol and rapamycin). Using the high-throughput screening method, we screened a library of 162 chemical entities and identified three compounds that extend the longevity of human cells.
    Keywords:  2,5-Anhydro-D-mannitol; Anti-aging; Chemical screening; Chronological lifespan; High-throughput methods; Human cells; Longevity; Rapamycin
    DOI:  https://doi.org/10.1186/s13062-024-00455-4
  27. bioRxiv. 2024 Jan 12. pii: 2024.01.11.575206. [Epub ahead of print]
    Neuronal microstructural changes in the human brain are associated with neurocognitive aging.
    Kavita Singh, Stephanie Barsoum, Kurt G Schilling, Yang An, Luigi Ferrucci, Dan Benjamini.
      Gray matter (GM) alterations play a role in aging-related disorders like Alzheimer's disease and related dementias, yet MRI studies mainly focus on macroscopic changes. Although reliable indicators of atrophy, morphological metrics like cortical thickness lack the sensitivity to detect early changes preceding visible atrophy. Our study aimed at exploring the potential of diffusion MRI in unveiling sensitive markers of cortical and subcortical age-related microstructural changes and assessing their associations with cognitive and behavioral deficits. We leveraged the Human Connectome Project-Aging cohort that included 707 unimpaired participants (394 female; median age = 58, range = 36-90 years) and applied the powerful mean apparent diffusion propagator model to measure microstructural parameters, along with comprehensive behavioral and cognitive test scores. Both macro- and microstructural GM characteristics were strongly associated with age, with widespread significant microstructural correlations reflective of cellular morphological changes, reduced cellular density, increased extracellular volume, and increased membrane permeability. Importantly, when correlating MRI and cognitive test scores, our findings revealed no link between macrostructural volumetric changes and neurobehavioral performance. However, we found that cellular and extracellular alterations in cortical and subcortical GM regions were associated with neurobehavioral performance. Based on these findings, it is hypothesized that increased microstructural heterogeneity and decreased neurite orientation dispersion precede macrostructural changes, and that they play an important role in subsequent cognitive decline. These alterations are suggested to be early markers of neurocognitive performance that may distinctly aid in identifying the mechanisms underlying phenotypic aging and subsequent age-related functional decline.
    Keywords:  MRI; aging; diffusion; gray matter; microstructure; neurocognitive aging
    DOI:  https://doi.org/10.1101/2024.01.11.575206
  28. J Clin Med. 2024 Jan 06. pii: 322. [Epub ahead of print]13(2):
    SA-β-Gal in Kidney Tubules as a Predictor of Renal Outcome in Patients with Chronic Kidney Disease.
    Pasquale Esposito, Daniela Picciotto, Daniela Verzola, Giacomo Garibotto, Emanuele Luigi Parodi, Antonella Sofia, Francesca Costigliolo, Gabriele Gaggero, Valentina Zanetti, Michela Saio, Francesca Viazzi.
      Cellular senescence has emerged as an important driver of aging and age-related disease in the kidney. The activity of β-galactosidase at pH 6 (SA-β-Gal) is a classic maker of senescence in cellular biology; however, the predictive role of kidney tissue SA-β-Gal on eGFR loss in chronic kidney disease (CKD) is still not understood. We retrospectively studied the expression of SA-β-Gal in kidney biopsies obtained in a cohort [n = 22] of incident patients who were followed up for 3 years as standard of care. SA-β-Gal staining was approximately fourfold higher in the tubular compartment of patients with CKD vs. controls [26.0 ± 9 vs. 7.4 ± 6% positive tubuli in patients vs. controls; p < 0.025]. Tubular expressions of SA-β-Gal, but not proteinuria, at the time of biopsy correlated with eGFR loss at the follow up; moreover, SA-β-Gal expression in more than 30% of kidney tubules was associated with fast progressive kidney disease. In conclusion, our study shows that SA-β-Gal is upregulated in the kidney tubular compartment of adult patients affected by CKD and suggests that tubular SA-β-Gal is associated with accelerated loss of renal function.
    Keywords:  cell; chronic kidney disease; kidney tubules; senescence
    DOI:  https://doi.org/10.3390/jcm13020322
  29. Immun Ageing. 2024 Jan 27. 21(1): 10
    Chitosan alleviates ovarian aging by enhancing macrophage phagocyte-mediated tissue homeostasis.
    Hui-Hui Shen, Xin-Yan Zhang, Nan Liu, Yang-Yang Zhang, Hui-Hua Wu, Feng Xie, Wen-Jun Wang, Ming-Qing Li.
       BACKGROUND: Age-related changes in the ovarian microenvironment are linked to impaired fertility in women. Macrophages play important roles in ovarian tissue homeostasis and immune surveillance. However, the impact of aging on ovarian macrophage function and ovarian homeostasis remains poorly understood.
    METHODS: Senescence-associated beta-galactosidase staining, immunohistochemistry, and TUNEL staining were used to assess senescence and apoptosis, respectively. Flow cytometry was employed to evaluate mitochondrial membrane potential (MMP) and apoptosis in granulosa cells lines (KGN), and macrophages phagocytosis. After a 2-month treatment with low molecular weight Chitosan (LMWC), ovarian tissues from mice were collected for comprehensive analysis.
    RESULTS: Compared with the liver and uterus, the ovary displayed accelerated aging in an age-dependent manner, which was accompanied by elevated levels of inflammatory factors and apoptotic cells, and impaired macrophage phagocytic activity. The aged KGN cells exhibited elevated reactive oxygen species (ROS) and apoptotic levels alongside decreased MMP. H2O2-induced aging macrophages showed reduced phagocytosis function. Moreover, there were excessive aging macrophages with impaired phagocytosis in the follicular fluid of patients with diminished ovarian reserve (DOR). Notably, LMWC administration alleviated ovarian aging by enhancing macrophage phagocytosis and promoting tissue homeostasis.
    CONCLUSIONS: Aging ovarian is characterized by an accumulation of aging and apoptotic granulosa cells, an inflammatory response and macrophage phagocytosis dysfunction. In turn, impaired phagocytosis of macrophage contributes to insufficient clearance of aging and apoptotic granulosa cells and the increased risk of DOR. Additionally, LMWC emerges as a potential therapeutic strategy for age-related ovarian dysfunction.
    Keywords:  Aging; phagocytosis; Chitosan; Diminished ovarian reserve; Macrophages; Ovary
    DOI:  https://doi.org/10.1186/s12979-024-00412-9
  30. Bone Res. 2024 Jan 25. 12(1): 6
    Age-related secretion of grancalcin by macrophages induces skeletal stem/progenitor cell senescence during fracture healing.
    Nan-Yu Zou, Ran Liu, Mei Huang, Yu-Rui Jiao, Jie Wei, Yangzi Jiang, Wen-Zhen He, Min Huang, Yi-Li Xu, Ling Liu, Yu-Chen Sun, Mi Yang, Qi Guo, Yan Huang, Tian Su, Ye Xiao, Wei-Shan Wang, Chao Zeng, Guang-Hua Lei, Xiang-Hang Luo, Chang-Jun Li.
      Skeletal stem/progenitor cell (SSPC) senescence is a major cause of decreased bone regenerative potential with aging, but the causes of SSPC senescence remain unclear. In this study, we revealed that macrophages in calluses secrete prosenescent factors, including grancalcin (GCA), during aging, which triggers SSPC senescence and impairs fracture healing. Local injection of human rGCA in young mice induced SSPC senescence and delayed fracture repair. Genetic deletion of Gca in monocytes/macrophages was sufficient to rejuvenate fracture repair in aged mice and alleviate SSPC senescence. Mechanistically, GCA binds to the plexin-B2 receptor and activates Arg2-mediated mitochondrial dysfunction, resulting in cellular senescence. Depletion of Plxnb2 in SSPCs impaired fracture healing. Administration of GCA-neutralizing antibody enhanced fracture healing in aged mice. Thus, our study revealed that senescent macrophages within calluses secrete GCA to trigger SSPC secondary senescence, and GCA neutralization represents a promising therapy for nonunion or delayed union in elderly individuals.
    DOI:  https://doi.org/10.1038/s41413-023-00309-1
  31. Biochem Genet. 2024 Jan 25.
    Molecular Network Mechanism Analysis of Urine Stem Cells Against Retinal Aging.
    Ning Bi, Na Li, Hua Liu, Ting-Hua Wang.
      To investigate the effect and potential mechanism of human-derived urine stem cells (hUSCs) in inhibiting retinal aging by using experimental and bioinformatics. Retinal pigment epithelial cells cultured in vitro, which were randomly divided into normal group, aging group and supernatant of hUSCs group. Cell counting kit-8 detection, senescence-related β-galactosidase, and Annexin V/PI staining were performed to detect cell viability, senescence, and apoptosis. Subsequently, bioinformatics methods were used to explore the underlying mechanisms, in which, targets both hUSCs and aging retina-related targets were obtained from GeneCards. Then, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and protein-protein interaction network were analysis, and the expressional level of hub gene was validated by q-PCR. Supernatant addition of hUSCs promoted markedly cellular proliferation, improved viability and inhibited senescence and apoptosis in vitro. A total of 1476 hUSCs-related targets (Relevance score > 20), 692 retinal disease-related targets, and 732 targets related to disease of aging were selected from GeneCards database, and 289 common targets of hUSCs against aging retina were confirmed through Venn analysis. Enrichment analysis demonstrated that hUSCs might exert its anti-apoptosis efficacy in multiple biological processes, including oxidative stress, inflammation and apoptosis, and core targets were associated with HIF-1, MAPK and PI3K-Akt signal. hUSCs inhibited retinal senescence by regulating multiply targets and signaling pathways, of these, HIF-1, MAPK, and PI3K may be important candidates.
    Keywords:  Aging; Bioinformatics; Human-derived urine stem cells; Retina; Retinal pigment epithelial cells
    DOI:  https://doi.org/10.1007/s10528-023-10487-6
  32. Antioxidants (Basel). 2023 Dec 25. pii: 42. [Epub ahead of print]13(1):
    The Binding of HSPA8 and Mitochondrial ALDH2 Mediates Oxygen-Glucose Deprivation-Induced Fibroblast Senescence.
    Wenting Hui, Tongtong Song, Ling Yu, Xia Chen.
      Cellular senescence refers to the permanent and irreversible cessation of the cell cycle. Recently, it has gained significant interest as a promising target for preventing cardiovascular diseases. Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that has been closely linked with an increased risk of cardiovascular diseases. In this study, bioinformatics analysis revealed that the signaling pathway for fibroblast senescence is significantly activated in mice after myocardial infarction (MI), and that ALDH2 might be a crucial molecule responsible for inducing this change. Therefore, we created an NIH3T3 fibroblast cell line oxygen-glucose deprivation (OGD) model to replicate the conditions of MI in vitro. We further revealed that decreased ALDH2 enzyme activity is a critical factor that affects fibroblast senescence after OGD, and the activation of ALDH2 can improve the mitochondrial damage caused by OGD. We identified Heat Shock 70-kDa Protein 8 (HSPA8) as an interacting protein of ALDH2 through co-immunoprecipitation (Co-IP) and mass spectrometry (MS) detection. Subsequently, our studies showed that HSPA8 translocates to the mitochondria after OGD, potentially binding to ALDH2 and inhibiting its enzyme activity. By transfecting siRNA to inhibit HSPA8 expression in cells, it was found that ALDH2 enzyme activity can be significantly increased, and the senescence characteristics induced by OGD in NIH3T3 cells can be improved. In conclusion, the data from this study suggest that HSPA8, in conjunction with ALDH2, could regulate fibroblast senescence after oxygen-glucose deprivation, providing a new direction and foundation for effectively intervening in fibroblast senescence after myocardial infarction.
    Keywords:  ALDH2; HSPA8; cellular senescence; oxygen-glucose deprivation
    DOI:  https://doi.org/10.3390/antiox13010042
  33. Cancers (Basel). 2024 Jan 19. pii: 431. [Epub ahead of print]16(2):
    ELF5: A Molecular Clock for Breast Aging and Cancer Susceptibility.
    Masaru Miyano, Mark A LaBarge.
      Breast cancer is predominantly an age-related disease, with aging serving as the most significant risk factor, compounded by germline mutations in high-risk genes like BRCA1/2. Aging induces architectural changes in breast tissue, particularly affecting luminal epithelial cells by diminishing lineage-specific molecular profiles and adopting myoepithelial-like characteristics. ELF5 is an important transcription factor for both normal breast and breast cancer development. This review focuses on the role of ELF5 in normal breast development, its altered expression throughout aging, and its implications in cancer. It discusses the lineage-specific expression of ELF5, its regulatory mechanisms, and its potential as a biomarker for breast-specific biological age and cancer risk.
    Keywords:  ELF5; aging; breast cancer; breast-specific biomarker; early detection biomarker; mammary epithelia
    DOI:  https://doi.org/10.3390/cancers16020431
  34. Biomedicines. 2024 Jan 10. pii: 143. [Epub ahead of print]12(1):
    Suppression of Bcl3 Disrupts Viability of Breast Cancer Cells through Both p53-Dependent and p53-Independent Mechanisms via Loss of NF-κB Signalling.
    Daniel J Turnham, Hannah Smith, Richard W E Clarkson.
      The NF-κB co-factor Bcl3 is a proto-oncogene that promotes breast cancer proliferation, metastasis and therapeutic resistance, yet its role in breast cancer cell survival is unclear. Here, we sought to determine the effect of Bcl3 suppression alone on breast cancer cell viability, with a view to informing future studies that aim to target Bcl3 therapeutically. Bcl3 was suppressed by siRNA in breast cancer cell lines before changes in viability, proliferation, apoptosis and senescence were examined. Bcl3 suppression significantly reduced viability and was shown to induce apoptosis in all cell lines tested, while an additional p53-dependent senescence and senescence-associated secretory phenotype was also observed in those cells with functional p53. The role of the Bcl3/NF-κB axis in this senescence response was confirmed via siRNA of the non-canonical NF-κB subunit NFKB2/p52, which resulted in increased cellular senescence and the canonical subunit NFKB1/p50, which induced the senescence-associated secretory phenotype. An analysis of clinical data showed a correlation between reduced relapse-free survival in patients that expressed high levels of Bcl3 and carried a p53 mutation. Together, these data demonstrate a dual role for Bcl3/NF-κB in the maintenance of breast cancer cell viability and suggests that targeting Bcl3 may be more beneficial to patients with tumours that lack functional p53.
    Keywords:  Bcl3; NF-κB; SASP; apoptosis; breast cancer; p53; senescence
    DOI:  https://doi.org/10.3390/biomedicines12010143
  35. iScience. 2024 Jan 19. 27(1): 108681
    HDAC1/2 inhibitor therapy improves multiple organ systems in aged mice.
    Alessandra Tammaro, Eileen G Daniels, Iman M Hu, Kelly C 't Hart, Kim Reid, Rio P Juni, Loes M Butter, Goutham Vasam, Rashmi Kamble, Aldo Jongejan, Richard I Aviv, Joris J T H Roelofs, Eleonora Aronica, Reinier A Boon, Keir J Menzies, Riekelt H Houtkooper, Georges E Janssens.
      Aging increases the risk of age-related diseases, imposing substantial healthcare and personal costs. Targeting fundamental aging mechanisms pharmacologically can promote healthy aging and reduce this disease susceptibility. In this work, we employed transcriptome-based drug screening to identify compounds emulating transcriptional signatures of long-lived genetic interventions. We discovered compound 60 (Cmpd60), a selective histone deacetylase 1 and 2 (HDAC1/2) inhibitor, mimicking diverse longevity interventions. In extensive molecular, phenotypic, and bioinformatic assessments using various cell and aged mouse models, we found Cmpd60 treatment to improve age-related phenotypes in multiple organs. Cmpd60 reduces renal epithelial-mesenchymal transition and fibrosis in kidney, diminishes dementia-related gene expression in brain, and enhances cardiac contractility and relaxation for the heart. In sum, our two-week HDAC1/2 inhibitor treatment in aged mice establishes a multi-tissue, healthy aging intervention in mammals, holding promise for therapeutic translation to promote healthy aging in humans.
    Keywords:  Drugs; Epigenetics; Molecular biology; Omics; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2023.108681
  36. Mol Neurobiol. 2024 Jan 23.
    Potential Roles of Nr4a3-Mediated Inflammation in Immunological and Neurological Diseases.
    Siqi He, Weijie Jiang, Baoyi Jiang, Chunyan Yu, Guifang Zhao, Yifei Li, Ling Qi, Jia Zhang, Dan Wang.
      As a protein of the orphan nuclear receptor Nr4a family, Nr4a3 has no identified natural ligands. However, its biological activity can be mediated by inducing conformational changes through interactions with specific certain small molecules and receptors. Nr4a3 is activated as an early stress factor under various pathological conditions and plays a regulatory role in various tissues and cells, participating in processes such as cell differentiation, apoptosis, metabolism, and homeostasis. At present, research on the role of Nr4a3 in the pathophysiology of inflammation is considerably limited, especially with respect to its role in the central nervous system (CNS). In this review, we discuss the role of Nr4a3 in multiple sclerosis, Alzheimer's disease, retinopathy, Parkinson's disease, and other CNS diseases. This review shows that Nr4a3 has considerable potential as a therapeutic target in the treatment of CNS diseases. We provide a theoretical basis for the targeted therapy of CNS diseases and neuroinflammation, among other conditions.
    Keywords:  Alzheimer’s disease; Central nervous system; Inflammation; Multiple sclerosis; Nr4a3; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s12035-024-03945-8
  37. Exp Cell Res. 2024 Jan 20. pii: S0014-4827(24)00022-3. [Epub ahead of print]435(2): 113932
    RBM10 regulates the tumorigenic potential of human cancer cells by modulating PPM1B and YBX1 activities.
    Yueyang Li, Di Wei, Zixiang Chen, Yukun Chen, Yuchun Deng, Mengge Li, Yongliang Zhao, Kaifeng Niu.
      RNA binding protein RBM10 participates in various RNA metabolism, and its decreased expression or loss of function by mutation has been identified in many human cancers. However, how its dysregulation contributes to human cancer pathogenesis remains to be determined. Here, we found that RBM10 expression was decreased in breast tumors, and breast cancer patients with low RBM10 expression presented poorer survival rates. RBM10 depletion in breast cancer cells significantly promotes the cellular proliferation and migration. We further demonstrated that RBM10 forms a triple complex with YBX1 and phosphatase 1B (PPM1B), in which PPM1B serves as the phosphatase of YBX1. RBM10 knock-down markedly attenuated association between YBX1 and PPM1B, leading to elevated levels of YBX1 phosphorylation and its nuclear translocation. Furthermore, cancer cells with RBM10 depletion had a significantly accelerated tumor growth in nude mice. Importantly, these enhanced tumorigenic phenotypes can be reversed by overexpression of PPM1B. Our findings provide the mechanistic bases for functional loss of RBM10 in promoting tumorigenicity, and are potentially useful in the development of combined therapeutic strategies for cancer patients with defective RBM10.
    Keywords:  Dephosphorylation; Protein phosphatase 1B; RNA binding motif protein 10; Tumorigenicity; Y-box-binding protein 1 phosphorylation
    DOI:  https://doi.org/10.1016/j.yexcr.2024.113932
  38. Nucleic Acids Res. 2024 Jan 23. pii: gkae023. [Epub ahead of print]
    Uncovering the roles of DNA hemi-methylation in transcriptional regulation using MspJI-assisted hemi-methylation sequencing.
    Xiong Xiong, Hengye Chen, Qifan Zhang, Yangying Liu, Chenhuan Xu.
      Hemi-methylated cytosine dyads widely occur on mammalian genomic DNA, and can be stably inherited across cell divisions, serving as potential epigenetic marks. Previous identification of hemi-methylation relied on harsh bisulfite treatment, leading to extensive DNA degradation and loss of methylation information. Here we introduce Mhemi-seq, a bisulfite-free strategy, to efficiently resolve methylation status of cytosine dyads into unmethylation, strand-specific hemi-methylation, or full-methylation. Mhemi-seq reproduces methylomes from bisulfite-based sequencing (BS-seq & hpBS-seq), including the asymmetric hemi-methylation enrichment flanking CTCF motifs. By avoiding base conversion, Mhemi-seq resolves allele-specific methylation and associated imprinted gene expression more efficiently than BS-seq. Furthermore, we reveal an inhibitory role of hemi-methylation in gene expression and transcription factor (TF)-DNA binding, and some displays a similar extent of inhibition as full-methylation. Finally, we uncover new hemi-methylation patterns within Alu retrotransposon elements. Collectively, Mhemi-seq can accelerate the identification of DNA hemi-methylation and facilitate its integration into the chromatin environment for future studies.
    DOI:  https://doi.org/10.1093/nar/gkae023
  39. J Nutr Biochem. 2024 Jan 18. pii: S0955-2863(24)00016-0. [Epub ahead of print] 109583
    Very low-carbohydrate diet with higher protein ratio improves lipid metabolism and inflammation in rats with diet-induced nonalcoholic fatty liver disease.
    I-Ting Wu, Wan-Ju Yeh, Wen-Chih Huang, Hsin-Yi Yang.
      Non-alcoholic fatty liver disease (NAFLD) is commonly associated with obesity, and it is mainly treated through lifestyle modifications. The very low-carbohydrate diet (VLCD) can help lose weight rapidly but the possible effects of extreme dietary patterns on lipid metabolism and inflammatory responses in individuals with NAFLD remain debatable. Moreover, VLCD protein content may affect its effectiveness in weight loss, steatosis, and inflammatory responses. Therefore, we investigated the effects of VLCDs with different protein contents in NAFLD rats and the mechanisms underlying these effects. After a 16-week inducing period, the rats received an isocaloric normal diet (NC group) or a VLCD with high or low protein content (NVLH vs. NVLL group, energy ratio: protein/carbohydrate/lipid = 20/1/79 vs. 6/1/93) protein content for the next 8 weeks experimental period. We noted that the body weight decreased in both the NVLH and NVLL groups; nevertheless, the NVLH group demonstrated improvements in ketosis. The NVLL group led to hepatic lipid accumulation, possibly by increasing very-low-density lipoprotein receptor (VLDLR) expression and elevating liver oxidative stress, subsequently activating the expression of Nrf2, and inflammation through the TLR4/TRIF/NLRP3 and TLR4/MyD88/NF-κB pathway. The NVLH was noted to prevent the changes in VLDLR and the TLR4-inflammasome pathway partially. The VLCD also reduced the diversity of gut microbiota and changed their composition. In conclusion, although low-protein VLCD consumption reduces BW, it may also lead to metabolic disorders and changes in microbiota composition; nevertheless, a VLCD with high protein content may partially alleviate these limitations.
    Keywords:  Gut microbiota; Inflammation; Nonalcoholic fatty liver disease; Protein; Steatosis; Very low-carbohydrate diet
    DOI:  https://doi.org/10.1016/j.jnutbio.2024.109583
  40. Antioxidants (Basel). 2024 Jan 14. pii: 101. [Epub ahead of print]13(1):
    C2CD4B Evokes Oxidative Stress and Vascular Dysfunction via a PI3K/Akt/PKCα-Signaling Pathway.
    Paola Di Pietro, Angela Carmelita Abate, Valeria Prete, Antonio Damato, Eleonora Venturini, Maria Rosaria Rusciano, Carmine Izzo, Valeria Visco, Michele Ciccarelli, Carmine Vecchione, Albino Carrizzo.
      High glucose-induced endothelial dysfunction is an important pathological feature of diabetic vasculopathy. While genome-wide studies have identified an association between type 2 diabetes mellitus (T2DM) and increased expression of a C2 calcium-dependent domain containing 4B (C2CD4B), no study has yet explored the possible direct effect of C2CD4B on vascular function. Vascular reactivity studies were conducted using a pressure myograph, and nitric oxide and oxidative stress were assessed through difluorofluorescein diacetate and dihydroethidium, respectively. We demonstrate that high glucose upregulated both mRNA and protein expression of C2CD4B in mice mesenteric arteries in a time-dependent manner. Notably, the inhibition of C2CD4B expression by genetic knockdown efficiently prevented hyperglycemia-induced oxidative stress, endothelial dysfunction, and loss of nitric oxide (NO) bioavailability. Recombinant C2CD4B evoked endothelial dysfunction of mice mesenteric arteries, an effect associated with increased reactive oxygen species (ROS) and decreased NO production. In isolated human umbilical vein endothelial cells (HUVECs), C2CD4B increased phosphorylation of endothelial nitric oxide synthase (eNOS) at the inhibitory site Thr495 and reduced eNOS dimerization. Pharmacological inhibitors of phosphoinositide 3-kinase (PI3K), Akt, and PKCα effectively attenuated oxidative stress, NO reduction, impairment of endothelial function, and eNOS uncoupling induced by C2CD4B. These data demonstrate, for the first time, that C2CD4B exerts a direct effect on vascular endothelium via a phosphoinositide 3-kinase (PI3K)/Akt/PKCα-signaling pathway, providing a new perspective on C2CD4B as a promising therapeutic target for the prevention of oxidative stress in diabetes-induced endothelial dysfunction.
    Keywords:  C2CD4B; diabetes; eNOS uncoupling; endothelial dysfunction; oxidative stress
    DOI:  https://doi.org/10.3390/antiox13010101
  41. Ageing Res Rev. 2024 Jan 24. pii: S1568-1637(24)00024-2. [Epub ahead of print] 102206
    PARP1 at the crossroad of cellular senescence and nucleolar processes.
    Kinga Kołacz, Agnieszka Robaszkiewicz.
      Senescent cells that occur in response to telomere shortening, oncogenes, extracellular and intracellular stress factors are characterized by permanent cell cycle arrest, the morphological and structural changes of the cell that include the senescence-associated secretory phenotype (SASP) and nucleoli rearrangement. The associated DNA lesions induce DNA damage response (DDR), which activates the DNA repair protein - poly-ADP-ribose polymerase 1 (PARP1). This protein consumes NAD+ to synthesize ADP-ribose polymer (PAR) on its own protein chain and on other interacting proteins. The involvement of PARP1 in nucleoli processes, such as rRNA transcription and ribosome biogenesis, the maintenance of heterochromatin and nucleoli structure, as well as controlling the crucial DDR protein release from the nucleoli to nucleus, links PARP1 with cellular senescence and nucleoli functioning. In this review we describe and discuss the impact of PARP1-mediated ADP-ribosylation on early cell commitment to senescence with the possible role of senescence-induced PARP1 transcriptional repression and protein degradation on nucleoli structure and function. The cause-effect interplay between PARP1 activation/decline and nucleoli functioning during senescence needs to be studied in detail.
    Keywords:  PARP1; cellular stress; nucleolus; senescence
    DOI:  https://doi.org/10.1016/j.arr.2024.102206
  42. Biomedicines. 2024 Jan 08. pii: 127. [Epub ahead of print]12(1):
    Anti-Aging Drugs and the Related Signal Pathways.
    Nannan Du, Ruigang Yang, Shengrong Jiang, Zubiao Niu, Wenzhao Zhou, Chenyu Liu, Lihua Gao, Qiang Sun.
      Aging is a multifactorial biological process involving chronic diseases that manifest from the molecular level to the systemic level. From its inception to 31 May 2022, this study searched the PubMed, Web of Science, EBSCO, and Cochrane library databases to identify relevant research from 15,983 articles. Multiple approaches have been employed to combat aging, such as dietary restriction (DR), exercise, exchanging circulating factors, gene therapy, and anti-aging drugs. Among them, anti-aging drugs are advantageous in their ease of adherence and wide prevalence. Despite a shared functional output of aging alleviation, the current anti-aging drugs target different signal pathways that frequently cross-talk with each other. At present, six important signal pathways were identified as being critical in the aging process, including pathways for the mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), nutrient signal pathway, silent information regulator factor 2-related enzyme 1 (SIRT1), regulation of telomere length and glycogen synthase kinase-3 (GSK-3), and energy metabolism. These signal pathways could be targeted by many anti-aging drugs, with the corresponding representatives of rapamycin, metformin, acarbose, nicotinamide adenine dinucleotide (NAD+), lithium, and nonsteroidal anti-inflammatory drugs (NSAIDs), respectively. This review summarized these important aging-related signal pathways and their representative targeting drugs in attempts to obtain insights into and promote the development of mechanism-based anti-aging strategies.
    Keywords:  NAD+; NSAIDS; acarbose; aging; anti-aging drugs; lithium; metformin; rapamycin; signal pathway
    DOI:  https://doi.org/10.3390/biomedicines12010127
  43. Nat Commun. 2024 Jan 26. 15(1): 775
    A renal clearable fluorogenic probe for in vivo β-galactosidase activity detection during aging and senolysis.
    Sara Rojas-Vázquez, Beatriz Lozano-Torres, Alba García-Fernández, Irene Galiana, Ana Perez-Villalba, Pablo Martí-Rodrigo, M José Palop, Marcia Domínguez, Mar Orzáez, Félix Sancenón, Juan F Blandez, Isabel Fariñas, Ramón Martínez-Máñez.
      Accumulation of senescent cells with age leads to tissue dysfunction and related diseases. Their detection in vivo still constitutes a challenge in aging research. We describe the generation of a fluorogenic probe (sulfonic-Cy7Gal) based on a galactose derivative, to serve as substrate for β-galactosidase, conjugated to a Cy7 fluorophore modified with sulfonic groups to enhance its ability to diffuse. When administered to male or female mice, β-galactosidase cleaves the O-glycosidic bond, releasing the fluorophore that is ultimately excreted by the kidneys and can be measured in urine. The intensity of the recovered fluorophore reliably reflects an experimentally controlled load of cellular senescence and correlates with age-associated anxiety during aging and senolytic treatment. Interestingly, our findings with the probe indicate that the effects of senolysis are temporary if the treatment is discontinued. Our strategy may serve as a basis for developing fluorogenic platforms designed for easy longitudinal monitoring of enzymatic activities in biofluids.
    DOI:  https://doi.org/10.1038/s41467-024-44903-1
  44. Antioxidants (Basel). 2024 Jan 02. pii: 70. [Epub ahead of print]13(1):
    The Multifaceted Roles of NRF2 in Cancer: Friend or Foe?
    Christophe Glorieux, Cinthya Enríquez, Constanza González, Gabriela Aguirre-Martínez, Pedro Buc Calderon.
      Physiological concentrations of reactive oxygen species (ROS) play vital roles in various normal cellular processes, whereas excessive ROS generation is central to disease pathogenesis. The nuclear factor erythroid 2-related factor 2 (NRF2) is a critical transcription factor that regulates the cellular antioxidant systems in response to oxidative stress by governing the expression of genes encoding antioxidant enzymes that shield cells from diverse oxidative alterations. NRF2 and its negative regulator Kelch-like ECH-associated protein 1 (KEAP1) have been the focus of numerous investigations in elucidating whether NRF2 suppresses tumor promotion or conversely exerts pro-oncogenic effects. NRF2 has been found to participate in various pathological processes, including dysregulated cell proliferation, metabolic remodeling, and resistance to apoptosis. Herein, this review article will examine the intriguing role of phase separation in activating the NRF2 transcriptional activity and explore the NRF2 dual impacts on tumor immunology, cancer stem cells, metastasis, and long non-coding RNAs (LncRNAs). Taken together, this review aims to discuss the NRF2 multifaceted roles in both cancer prevention and promotion while also addressing the advantages, disadvantages, and limitations associated with modulating NRF2 therapeutically in cancer treatment.
    Keywords:  LncRNA; NRF2; NRF2 activators; NRF2 inhibitors; cancer; metabolism; metastasis; natural compounds; phase separation; tumor immunology
    DOI:  https://doi.org/10.3390/antiox13010070
  45. J Transl Med. 2024 Jan 20. 22(1): 82
    (+)-Lipoic acid reduces mitochondrial unfolded protein response and attenuates oxidative stress and aging in an in vitro model of non-alcoholic fatty liver disease.
    Lucia Longhitano, Alfio Distefano, Nicolò Musso, Paolo Bonacci, Laura Orlando, Sebastiano Giallongo, Daniele Tibullo, Simona Denaro, Giuseppe Lazzarino, Jessica Ferrigno, Anna Nicolosi, Amer M Alanazi, Federico Salomone, Emanuela Tropea, Ignazio Alberto Barbagallo, Vincenzo Bramanti, Giovanni Li Volti, Giacomo Lazzarino, Daniele Torella, Angela Maria Amorini.
       BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a liver disorder characterized by the ac-cumulation of fat in hepatocytes without alcohol consumption. Mitochondrial dysfunction and endoplasmic reticulum (ER) stress play significant roles in NAFLD pathogenesis. The unfolded protein response in mitochondria (UPRmt) is an adaptive mechanism that aims to restore mitochondrial protein homeostasis and mitigate cellular stress. This study aimed to investigate the effects of ( +)-Lipoic acid (ALA) on UPRmt, inflammation, and oxidative stress in an in vitro model of NAFLD using HepG2 cells treated with palmitic acid and oleic acid to induce steatosis.
    RESULTS: Treatment with palmitic and oleic acids increased UPRmt-related proteins HSP90 and HSP60 (heat shock protein), and decreased CLPP (caseinolytic protease P), indicating ER stress activation. ALA treatment at 1 μM and 5 μM restored UPRmt-related protein levels. PA:OA (palmitic acid:oleic acid)-induced ER stress markers IRE1α (Inositol requiring enzyme-1), CHOP (C/EBP Homologous Protein), BIP (Binding Immunoglobulin Protein), and BAX (Bcl-2-associated X protein) were significantly reduced by ALA treatment. ALA also enhanced ER-mediated protein glycosylation and reduced oxidative stress, as evidenced by decreased GPX1 (Glutathione peroxidase 1), GSTP1 (glutathione S-transferase pi 1), and GSR (glutathione-disulfide reductase) expression and increased GSH (Glutathione) levels, and improved cellular senescence as shown by the markers β-galactosidase, γH2Ax and Klotho-beta.
    CONCLUSIONS: In conclusion, ALA ameliorated ER stress, oxidative stress, and inflammation in HepG2 cells treated with palmitic and oleic acids, potentially offering therapeutic benefits for NAFLD providing a possible biochemical mechanism underlying ALA beneficial effects.
    Keywords:  Mitochondrial dysfunction; Non-alcoholic fatty liver disease; Oxidative stress; Unfolded protein re-sponse
    DOI:  https://doi.org/10.1186/s12967-024-04880-x
  46. Front Pharmacol. 2023 ;14 1309598
    Pharmacological functions of salidroside in renal diseases: facts and perspectives.
    Qiong Liu, Jianzhu Chen, Anqi Zeng, Linjiang Song.
      Rhodiola rosea is a valuable functional medicinal plant widely utilized in China and other Asian countries for its anti-fatigue, anti-aging, and altitude sickness prevention properties. Salidroside, a most active constituent derived from Rhodiola rosea, exhibits potent antioxidative, hypoxia-resistant, anti-inflammatory, anticancer, and anti-aging effects that have garnered significant attention. The appreciation of the pharmacological role of salidroside has burgeoned over the last decade, making it a beneficial option for the prevention and treatment of multiple diseases, including atherosclerosis, Alzheimer's disease, Parkinson's disease, cardiovascular disease, and more. With its anti-aging and renoprotective effects, in parallel with the inhibition of oxidative stress and inflammation, salidroside holds promise as a potential therapeutic agent for kidney damage. This article provides an overview of the microinflammatory state in kidney disease and discuss the current therapeutic strategies, with a particular focus on highlighting the recent advancements in utilizing salidroside for renal disease. The potential mechanisms of action of salidroside are primarily associated with the regulation of gene and protein expression in glomerular endothelial cells, podocytes, renal tubule cells, renal mesangial cells and renal cell carcinoma cell, including TNF-α, TGF-β, IL-1β, IL-17A, IL-6, MCP-1, Bcl-2, VEGF, ECM protein, caspase-3, HIF-1α, BIM, as well as the modulation of AMPK/SIRT1, Nrf2/HO-1, Sirt1/PGC-1α, ROS/Src/Cav-1, Akt/GSK-3β, TXNIP-NLRP3, ERK1/2, TGF-β1/Smad2/3, PI3K/Akt, Wnt1/Wnt3a β-catenin, TLR4/NF-κB, MAPK, JAK2/STAT3, SIRT1/Nrf2 pathways. To the best of our knowledge, this review is the first to comprehensively cover the protective effects of salidroside on diverse renal diseases, and suggests that salidroside has great potential to be developed as a drug for the prevention and treatment of metabolic syndrome, cardiovascular and cerebrovascular diseases and renal complications.
    Keywords:  acute kidney injury; diabetic nephropathy; inflammation; renal cell carcinoma; renal interstitial fibrosis; salidroside
    DOI:  https://doi.org/10.3389/fphar.2023.1309598
  47. Gerontology. 2024 Jan 19.
    The Trajectory of Successful Aging: Insights from Metagenome and Cytokine Profiling.
    Laura Chulenbayeva, Yuliya Ganzhula, Samat Kozhakhmetov, Zharkyn Jarmukhanov, Madiyar Nurgaziyev, Ayaulym Nurgozhina, Nurislam Muhanbetzhanov, Shynggys Sergazy, Sanzhar Zhetkenev, Zhanar Borykbay, Viktor Tkachev, Saltanat Urazova, Elizaveta Vinogradova, Almagul Kushugulova.
       INTRODUCTION: The longevity is influenced by of genetic, environmental, and lifestyle factors. The specific changes that occur in the gut microbiome during the aging process, and their relationship to longevity and immune function, have not yet been fully understood. The ongoing research other microbiome based to longevity cohort in Kazakhstan, provides preliminary information on longevity-related aging, where cytokine expression is associated with specific microbial communities and microbial functions.
    METHODS: Metagenomic shotgun sequencing study of 40 long-lived individuals aged 90 years and over were carried out, who were conditionally healthy and active, able to served themselves, without a history of serious infection and cancer, who had not taken any antimicrobials, including probiotics. Blood serum weas analyzed to clinical and laboratory characteristics. The cytokine and chemokine profile in serum and stool samples was assessed using Multiplex analysis.
    RESULTS: We found a significant increase in the expression of pro-inflammatory cytokines IL-1a, IL-6, 12p70, IP-10, IFN-α2, IL-15 TNFa, as well as chemokines MIP-1a/CCL3 and MIP-1b/CCL4, chemokine motif ligands MCP-3/CCL7 and MDC/CCL22(1c). Nonagenerians and centenarians demonstrated a greater diversity of core microbiota genera and showed an elevated prevalence of the genera Bacteroides, Clostridium, Escherichia and Alistipes. Conversely, there was a decrease in the abundance of the genera Ruminococcaceae, Fusicatenibacter, Dorea, as well as the species Fusicatenibacter saccharivorans. Furthermore, functional analysis revealed that the microbiome in long-lived group has a high capacity for lipid metabolism, amino acid degradation, and potential signs of chronic inflammatory status.
    CONCLUSION: Long-lived individuals exhibit an immune system imbalance and observed changes in the composition of the gut microbiota at the genus level between to the two age groups. Age-related changes in the gut microbiome, metabolic functions of the microbial community, and chronic inflammation all contribute to immunosenescence. In turn, the inflammatory state and microbial composition of the gut is related to nutritional status.
    DOI:  https://doi.org/10.1159/000536082
  48. Int J Mol Sci. 2024 Jan 05. pii: 718. [Epub ahead of print]25(2):
    Reduced SIRT1 and SIRT3 and Lower Antioxidant Capacity of Seminal Plasma Is Associated with Shorter Sperm Telomere Length in Oligospermic Men.
    Varinderpal S Dhillon, Mohammad Shahid, Permal Deo, Michael Fenech.
      Infertility affects millions of couples worldwide and has a profound impact not only on their families, but also on communities. Telomere attrition has been associated with infertility, DNA damage and fragmentation. Oxidative stress has been shown to affect sperm DNA integrity and telomere length. Sirtuins such as SIRT1 and SIRT3 are involved in aging and oxidative stress response. The aim of the present study is to determine the role of SIRT1 and SIRT3 in regulating oxidative stress, telomere shortening, and their association with oligospermia. Therefore, we assessed the protein levels of SIRT1 and SIRT3, total antioxidant capacity (TAC), superoxide dismutase (SOD), malondialdehyde (MDA) and catalase activity (CAT) in the seminal plasma of 272 patients with oligospermia and 251 fertile men. We also measured sperm telomere length (STL) and leukocyte telomere length (LTL) using a standard real-time quantitative PCR assay. Sperm chromatin and protamine deficiency were also measured as per standard methods. Our results for oligospermic patients demonstrate significant reductions in semen parameters, shorter STL and LTL, lower levels of SOD, TAC, CAT, SIRT1 and SIRT3 levels, and also significant protamine deficiency and higher levels of MDA and DNA fragmentation. We conclude that a shorter TL in sperms and leukocytes is associated with increased oxidative stress that also accounts for high levels of DNA fragmentation in sperms. Our results support the hypothesis that various sperm parameters in the state of oligospermia are associated with or caused by reduced levels of SIRT1 and SIRT3 proteins.
    Keywords:  antioxidant capacity; oxidative stress; seminal plasma; sperms; telomere length
    DOI:  https://doi.org/10.3390/ijms25020718
  49. Aging Cell. 2024 Jan 23. e14079
    DNA methylation and chromatin accessibility predict age in the domestic dog.
    Kelly Jin, Brianah M McCoy, Elisabeth A Goldman, Viktoria Usova, Victor Tkachev, Alex D Chitsazan, Anneke Kakebeen, Unity Jeffery, Kate E Creevy, Andrea Wills, Noah Snyder-Mackler, Daniel E L Promislow.
      Across mammals, the epigenome is highly predictive of chronological age. These "epigenetic clocks," most of which have been built using DNA methylation (DNAm) profiles, have gained traction as biomarkers of aging and organismal health. While the ability of DNAm to predict chronological age has been repeatedly demonstrated, the ability of other epigenetic features to predict age remains unclear. Here, we use two types of epigenetic information-DNAm, and chromatin accessibility as measured by ATAC-seq-to develop age predictors in peripheral blood mononuclear cells sampled from a population of domesticated dogs. We measured DNAm and ATAC-seq profiles for 71 dogs, building separate predictive clocks from each, as well as the combined dataset. We also use fluorescence-assisted cell sorting to quantify major lymphoid populations for each sample. We found that chromatin accessibility can accurately predict chronological age (R2 ATAC  = 26%), though less accurately than the DNAm clock (R2 DNAm  = 33%), and the clock built from the combined datasets was comparable to both (R2 combined  = 29%). We also observed various populations of CD62L+ T cells significantly correlated with dog age. Finally, we found that all three clocks selected features that were in or near at least two protein-coding genes: BAIAP2 and SCARF2, both previously implicated in processes related to cognitive or neurological impairment. Taken together, these results highlight the potential of chromatin accessibility as a complementary epigenetic resource for modeling and investigating biologic age.
    Keywords:  ATAC-seq; DNA methylation; aging; dogs; epigenetic clock
    DOI:  https://doi.org/10.1111/acel.14079
  50. Antioxidants (Basel). 2024 Jan 05. pii: 76. [Epub ahead of print]13(1):
    Heavy Metal Exposure: Molecular Pathways, Clinical Implications, and Protective Strategies.
    Hajime Koyama, Teru Kamogashira, Tatsuya Yamasoba.
      Heavy metals are often found in soil and can contaminate drinking water, posing a serious threat to human health. Molecular pathways and curation therapies for mitigating heavy metal toxicity have been studied for a long time. Recent studies on oxidative stress and aging have shown that the molecular foundation of cellular damage caused by heavy metals, namely, apoptosis, endoplasmic reticulum stress, and mitochondrial stress, share the same pathways as those involved in cellular senescence and aging. In recent aging studies, many types of heavy metal exposures have been used in both cellular and animal aging models. Chelation therapy is a traditional treatment for heavy metal toxicity. However, recently, various antioxidants have been found to be effective in treating heavy metal-induced damage, shifting the research focus to investigating the interplay between antioxidants and heavy metals. In this review, we introduce the molecular basis of heavy metal-induced cellular damage and its relationship with aging, summarize its clinical implications, and discuss antioxidants and other agents with protective effects against heavy metal damage.
    Keywords:  aging; antioxidants; cellular damage; heavy metal toxicity
    DOI:  https://doi.org/10.3390/antiox13010076
  51. Drug Alcohol Depend. 2024 Jan 17. pii: S0376-8716(24)00015-2. [Epub ahead of print]256 111094
    Methamphetamine use shortens telomere length in male adults and rats.
    Guanyi Lu, Ting Fang, Xinyue Li, XiaoJie Zhang, Hong Li, Ning Wu, Feng Liu, Wei Hao, Qi-Nong Ye, Long Cheng, Jin Li, Fei Li.
       BACKGROUND: Methamphetamine (MA) use increases the risk of age-related diseases. However, it remains uncertain whether MA use exhibits accelerated biological aging, as indicated by telomere length (TL), a proposed marker of aging. Here we conducted studies in both humans and rats to investigate the association between MA use and TL.
    METHODS: We recruited 125 male MA users and 66 healthy controls, aged 30-40 years. MA users were diagnosed using DSM-5 criteria and categorized into two groups: non-severe (n = 78) and severe (n = 47) MA use disorder (MUD). MA-treated conditioned place preference (CPP) rats were utilized to validate our clinical investigations. TL was assessed using real-time polymerase chain reaction.
    RESULTS: At clinical levels, MA users exhibited significantly shorter leukocyte TL compared to healthy controls. Among MA users, individuals with severe MUD had significantly shorter leukocyte TL than those with non-severe MUD. Importantly, both univariate and multivariate linear regression analyses demonstrated a negative association between the severity of MA use and leukocyte TL. In a rat model of MA-induced CPP, leukocyte TL was also significantly shortened after MA administration, especially in rats with higher CPP expression or reinstatement scores.
    CONCLUSION: MA use shortened TL, and the severity of MA use was negatively correlated with TL. These findings provide new insights into the pathophysiology of accelerated aging caused by MA use and may have implications for identifying biomarkers and developing novel treatment strategies for MUD.
    Keywords:  Conditioned place preference; Methamphetamine; Methamphetamine use disorder; Peripheral blood mononuclear cells; Telomere length
    DOI:  https://doi.org/10.1016/j.drugalcdep.2024.111094
  52. Mitochondrion. 2024 Jan 19. pii: S1567-7249(24)00001-1. [Epub ahead of print]75 101843
    DDQ anti-aging properties expressed with improved mitophagy in mutant tau HT22 neuronal cells.
    Jangampalli Adi Pradeepkiran, Priyanka Rawat, Arubala P Reddy, Erika Orlov, P Hemachandra Reddy.
      The purpose of our study is to develop age-related phosphorylated tau (p-tau) inhibitors, for Alzheimer's disease (AD). There are wide-ranging therapeutic molecules available in the market and tested for age-related p-tau inhibition to enhance phosphatase activity and microtubule stability in AD neurons. Until now there are no such small molecules claimed to show promising results to delay the disease process of AD. However, a recently developed molecule, DDQ, has been shown to reduce abnormal protein-protein interactions and protect neurons from mutant protein-induced toxicities in the disease process. In addition, DDQ reduced age- and Aβ-induced oxidative stress, mitochondrial dysfunction, and synaptic toxicity. To date, there are no published reports on the p-tau interaction of DDQ and Sirt3 upregulation with CREB-mediated mitophagy activation in AD neurons. In the current study, HT22 cells were transfected with mutant Tau (mTau) cDNA and treated with the novel molecule DDQ. Cell survival, immunoblotting, and immunofluorescence analysis were conducted to assess cell viability and synaptic and mitophagy proteins in treated and untreated cell groups. As expected, we found cell survival was decreased in mTau-HT22 cells when compared with control HT22 cells. However, cell survival was increased in DDQ-treated mTau-HT22 cells when compared with mTau HT22 cells. P-tau and total tau proteins were significantly reduced in DDQ-treated mTau-HT22 cells, and MAP2 levels were increased. Anti-aging proteins like Sirt3, and CREB levels were increased in DDQ-treated HT22 cells and also in mTau-HT22 cells treated DDQ. Mitophagy proteins were decreased in mTau-HT22 cells and these were increased in DDQ-treated mTau-HT22 cells. These observations strongly suggest that DDQ has anti-p-tau and anti-aging properties, via Sirt3 overexpression and increased mitophagy proteins. Our study findings may have implications for healthy aging to the development of p-tau targeted therapeutics in AD and tauopathies.
    Keywords:  Alzheimer’s disease; Anti-aging; DDQ; Mitophagy; Sirt3
    DOI:  https://doi.org/10.1016/j.mito.2024.101843
  53. Life (Basel). 2024 Jan 15. pii: 124. [Epub ahead of print]14(1):
    Protein-Protein Interactions of Seryl-tRNA Synthetases with Emphasis on Human Counterparts and Their Connection to Health and Disease.
    Morana Dulic, Vlatka Godinic-Mikulcic, Mario Kekez, Valentina Evic, Jasmina Rokov-Plavec.
      Seryl-tRNA synthetases (SerRSs), members of the aminoacyl-tRNA synthetase family, interact with diverse proteins, enabling SerRSs to enhance their role in the translation of the genetic message or to perform alternative functions in cellular processes beyond translation. Atypical archaeal SerRS interacts with arginyl-tRNA synthetase and proteins of the ribosomal P-stalk to optimize translation through tRNA channeling. The complex between yeast SerRS and peroxin Pex21p provides a connection between translation and peroxisome function. The partnership between Arabidopsis SerRS and BEN1 indicates a link between translation and brassinosteroid metabolism and may be relevant in plant stress response mechanisms. In Drosophila, the unusual heterodimeric mitochondrial SerRS coordinates mitochondrial translation and replication via interaction with LON protease. Evolutionarily conserved interactions of yeast and human SerRSs with m3C32 tRNA methyltransferases indicate coordination between tRNA modification and aminoacylation in the cytosol and mitochondria. Human cytosolic SerRS is a cellular hub protein connecting translation to vascular development, angiogenesis, lipogenesis, and telomere maintenance. When translocated to the nucleus, SerRS acts as a master negative regulator of VEGFA gene expression. SerRS alone or in complex with YY1 and SIRT2 competes with activating transcription factors NFκB1 and c-Myc, resulting in balanced VEGFA expression important for proper vascular development and angiogenesis. In hypoxia, SerRS phosphorylation diminishes its binding to the VEGFA promoter, while the lack of nutrients triggers SerRS glycosylation, reducing its nuclear localization. Additionally, SerRS binds telomeric DNA and cooperates with the shelterin protein POT1 to regulate telomere length and cellular senescence. As an antitumor and antiangiogenic factor, human cytosolic SerRS appears to be a promising drug target and therapeutic agent for treating cancer, cardiovascular diseases, and possibly obesity and aging.
    Keywords:  SARS1; VEGFA; aminoacyl-tRNA synthetase; angiogenesis; protein–protein interaction; senescence; seryl-tRNA synthetase; tRNA channeling; telomere; translation
    DOI:  https://doi.org/10.3390/life14010124
  54. Aging Biol. 2023 ;pii: 20230011. [Epub ahead of print]1(1):
    Hallmarks of Aging: Causes and Consequences.
    Dorota Skowronska-Krawczyk.
      In a recent review article published in Cell, López-Otín and colleagues conducted an exhaustive literature review and described 12 hallmarks of aging. The updated model of aging comprehensively captures the key characteristics of the aging phenotype and incorporates new pathways that play a crucial role in age-related processes. Although the updated hallmarks of aging provide a useful framework for describing the phenotype of aging, aging itself is a result of mechanistically complex and interrelated processes that happen during the lifespan of the organism. Here, I propose to shift the focus from a systematic description and categorization of the hallmarks of aging to a model that separates the early, molecular origins of changes from cellular and tissue responses and represents the sequential and causative character of changes in aging. The proposed model aims to prompt discussion among the aging research community, guide future efforts in the field, and provide new ideas for investigation.
    DOI:  https://doi.org/10.59368/agingbio.20230011
  55. Geroscience. 2024 Jan 24.
    Translatability of mouse muscle-aging for humans: the role of sex.
    Jelle C B C de Jong, Martien P M Caspers, Nicole Worms, Nanda Keijzer, Robert Kleemann, Aswin L Menke, Arie G Nieuwenhuizen, Jaap Keijer, Lars Verschuren, Anita M van den Hoek.
      Muscle-aging drives sarcopenia and is a major public health issue. Mice are frequently used as a model for human muscle-aging, however, research investigating their translational value is limited. In addition, mechanisms underlying muscle-aging may have sex-specific features in humans, but it is not yet assessed whether these are recapitulated in mice. Here, we studied the effects of aging on a functional, histological and transcriptional level at multiple timepoints in male and female mice (4, 17, 21 and 25 months), with particular emphasis on sex-differences. The effects of natural aging on the transcriptome of quadriceps muscle were compared to humans on pathway level. Significant loss of muscle mass occurred late, at 25 months, in both male (-17%, quadriceps) and female mice (-10%, quadriceps) compared to young control mice. Concomitantly, we found in female, but not male mice, a slower movement speed in the aged groups compared to the young mice (P < 0.001). Consistently, weighted gene co-expression network analysis revealed a stronger association between the aging-related reduction of movement and aging-related changes in muscle transcriptome of female compared to male mice (P < 0.001). In male, but not female mice, major distinctive aging-related changes occurred in the last age group (25 months), which highlights the necessity for careful selection of age using mice as a muscle-aging model. Furthermore, contrasting to humans, more aging-related changes were found in the muscle transcriptome of male mice compared to female mice (4090 vs. 2285 differentially expressed genes at 25 months, respectively). Subsequently, male mice recapitulated more muscle-aging related pathways characteristic for both male and female humans. In conclusion, our data show that sex has a critical effect on the mouse muscle-aging trajectory, although these do not necessarily reflect sex differences observed in the human muscle-aging trajectory.
    Keywords:  Frailty; Gender; Muscle atrophy; Physical activity; Sarcopenia
    DOI:  https://doi.org/10.1007/s11357-024-01082-7
  56. Neurosci Lett. 2024 Jan 24. pii: S0304-3940(24)00023-5. [Epub ahead of print] 137646
    Exercise-induced expression of genes associated with aging in the hippocampus of rats.
    Hyo Youl Moon, Minchul Lee.
      Recent research has underscored the influence of aging and exercise on brain function. In this study, we aimed to explore alterations in the expression of novel molecular factors and gain insight into underlying molecular mechanisms in the hippocampus of rats engaged in voluntary wheel running. We assessed the expression of aging-related genes in the hippocampus using a high-throughput whole genome DNA microarray approach in rats engaged in voluntary running for four weeks. The results indicated that compared to the control group, wheel running significantly altered the expressions of aging-related genes in the hippocampus. Functional categorization, utilizing pathway-focused gene classifications and disease state-focused gene classifications, along with Ingenuity Pathway Analysis (IPA), revealed changes in expression pattern in major categories of cell death and survival, renal necrosis/cell death, and cardiovascular disease genes. These findings suggest that exercise may mitigate the risk of age-related cognitive decline by regulating of aging-related genes in the hippocampus. Further research is warranted to elucidate the mechanisms driving changes in gene expression and to determine the long-term effects of exercise on brain function.
    Keywords:  Aging; DNA microarray; Exercise; Hippocampus; Neuronal plasticity
    DOI:  https://doi.org/10.1016/j.neulet.2024.137646
  57. Bioorg Med Chem. 2024 Jan 11. pii: S0968-0896(24)00009-9. [Epub ahead of print]99 117595
    Drug discovery targeting nicotinamide phosphoribosyltransferase (NAMPT): Updated progress and perspectives.
    Fei Wen, Gang Gui, Xiaoyu Wang, Li Ye, Anqi Qin, Chen Zhou, Xiaoming Zha.
      Nicotinamide phosphoribosyltransferase (NAMPT) is a key rate-limiting enzyme in the nicotinamide adenine dinucleotide (NAD+) salvage pathway, primarily catalyzing the synthesis of nicotinamide mononucleotide (NMN) from nicotinamide (NAM), phosphoribosyl pyrophosphate (PRPP), and adenosine triphosphate (ATP). Metabolic diseases, aging-related diseases, inflammation, and cancers can lead to abnormal expression levels of NAMPT due to the pivotal role of NAD+ in redox metabolism, aging, the immune system, and DNA repair. In addition, NAMPT can be secreted by cells as a cytokine that binds to cell membrane receptors to regulate intracellular signaling pathways. Furthermore, NAMPT is able to reduce therapeutic efficacy by enhancing acquired resistance to chemotherapeutic agents. Recently, a few novel activators and inhibitors of NAMPT for neuroprotection and anti-tumor have been reported, respectively. However, NAMPT activators are still in preclinical studies, and only five NAMPT inhibitors have entered the clinical stage, unfortunately, three of which were terminated or withdrawn due to safety concerns. Novel drug design strategies such as proteolytic targeting chimera (PROTAC), antibody-drug conjugate (ADC), and dual-targeted inhibitors also provide new directions for the development of NAMPT inhibitors. In this perspective, we mainly discuss the structure, biological function, and role of NAMPT in diseases and the currently discovered activators and inhibitors. It is our hope that this work will provide some guidance for the future design and optimization of NAMPT activators and inhibitors.
    Keywords:  Activators; Aging-related diseases; Anti-tumor; Inhibitors; Metabolism; NAMPT; Neuroprotection
    DOI:  https://doi.org/10.1016/j.bmc.2024.117595
  58. Front Microbiol. 2023 ;14 1257903
    The role of gut microbiota in the occurrence and progression of non-alcoholic fatty liver disease.
    Huanzhuo Mai, Xing Yang, Yulan Xie, Jie Zhou, Qing Wang, Yiru Wei, Yuecong Yang, Dongjia Lu, Li Ye, Ping Cui, Hao Liang, Jiegang Huang.
       Background: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent cause of chronic liver disease worldwide, and gut microbes are associated with the development and progression of NAFLD. Despite numerous studies exploring the changes in gut microbes associated with NAFLD, there was no consistent pattern of changes.
    Method: We retrieved studies on the human fecal microbiota sequenced by 16S rRNA gene amplification associated with NAFLD from the NCBI database up to April 2023, and re-analyzed them using bioinformatic methods.
    Results: We finally screened 12 relevant studies related to NAFLD, which included a total of 1,189 study subjects (NAFLD, n = 654; healthy control, n = 398; obesity, n = 137). Our results revealed a significant decrease in gut microbial diversity with the occurrence and progression of NAFLD (SMD = -0.32; 95% CI -0.42 to -0.21; p < 0.001). Alpha diversity and the increased abundance of several crucial genera, including Desulfovibrio, Negativibacillus, and Prevotella, can serve as an indication of their predictive risk ability for the occurrence and progression of NAFLD (all AUC > 0.7). The occurrence and progression of NAFLD are significantly associated with higher levels of LPS biosynthesis, tryptophan metabolism, glutathione metabolism, and lipid metabolism.
    Conclusion: This study elucidated gut microbes relevance to disease development and identified potential risk-associated microbes and functional pathways associated with NAFLD occurrence and progression.
    Keywords:  16S ribosomal RNA gene amplicon sequencing; gut microbiota; liver disease; microbial markers; nonalcoholic fatty liver disease
    DOI:  https://doi.org/10.3389/fmicb.2023.1257903
  59. Mol Vis. 2023 ;29 338-356
    Suppressor of cytokine signaling 3-derived peptide as a therapeutic for inflammatory and oxidative stress-induced damage to the retina.
    Chulbul M Ahmed, Anil P Patel, Howard M Johnson, Cristhian J Ildefonso, Alfred S Lewin.
       Purpose: Inflammation and oxidative stress contribute to age-related macular degeneration (AMD) and other retinal diseases. We tested a cell-penetrating peptide from the kinase inhibitory region of an intracellular checkpoint inhibitor suppressor of cytokine signaling 3 (R9-SOCS3-KIR) peptide for its ability to blunt the inflammatory or oxidative pathways leading to AMD.
    Methods: We used anaphylatoxin C5a to mimic the effect of activated complement, lipopolysaccharide (LPS), and tumor necrosis factor alpha (TNFα) to stimulate inflammation and paraquat to induce mitochondrial oxidative stress. We used a human retinal pigment epithelium (RPE) cell line (ARPE-19) as proliferating cells and a mouse macrophage cell line (J774A.1) to follow cell propagation using microscopy or cell titer assays. We evaluated inflammatory pathways by monitoring the nuclear translocation of NF-κB p65 and mitogen-activated protein kinase p38. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot were used to evaluate the induction of inflammatory markers. In differentiated ARPE-19 monolayers, we evaluated the integrity of tight junction proteins through microscopy and the measurement of transepithelial electrical resistance (TEER). We used intraperitoneal injection of sodium iodate in mice to test the ability of R9-SOC3-KIR to prevent RPE and retinal injury, as assessed by fundoscopy, optical coherence tomography, and histology.
    Results: R9-SOCS3-KIR treatment suppressed C5a-induced nuclear translocation of the NF-kB activation domain p65 in undifferentiated ARPE-19 cells. TNF-mediated damage to tight junction proteins in RPE, and the loss of TEER was prevented in the presence of R9-SOCS3-KIR. Treatment with the R9-SOCS3-KIR peptide blocked the C5a-induced expression of inflammatory genes. The R9-SOCS3-KIR treatment also blocked the LPS-induced expression of interleukin-6, MCP1, cyclooxygenase 2, and interleukin-1 beta. R9-SOCS3-KIR prevented paraquat-mediated cell death and enhanced the levels of antioxidant effectors. Daily eye drop treatment with R9-SOCS3-KIR protected against retinal injury caused by i.p. administration of sodium iodate.
    Conclusions: R9-SOCS3-KIR blocks the induction of inflammatory signaling in cell culture and reduces retinal damage in a widely used RPE/retinal oxidative injury model. As this peptide can be administered through corneal instillation, this treatment may offer a convenient way to slow down the progression of ocular diseases arising from inflammation and chronic oxidative stress.
  60. Int J Mol Sci. 2024 Jan 22. pii: 1328. [Epub ahead of print]25(2):
    Phosphorylation of Thr-225 and Ser-262 on ERD7 Promotes Age-Dependent and Stress-Induced Leaf Senescence through the Regulation of Hydrogen Peroxide Accumulation in Arabidopsis thaliana.
    Rongrong Wu, Xiaolu Pan, Wei Li, Zenglin Zhang, Yongfeng Guo.
      As the final stage of leaf development, leaf senescence is affected by a variety of internal and external signals including age and environmental stresses. Although significant progress has been made in elucidating the mechanisms of age-dependent leaf senescence, it is not clear how stress conditions induce a similar process. Here, we report the roles of a stress-responsive and senescence-induced gene, ERD7 (EARLY RESPONSIVE TO DEHYDRATION 7), in regulating both age-dependent and stress-induced leaf senescence in Arabidopsis. The results showed that the leaves of erd7 mutant exhibited a significant delay in both age-dependent and stress-induced senescence, while transgenic plants overexpressing the gene exhibited an obvious accelerated leaf senescence. Furthermore, based on the results of LC-MS/MS and PRM quantitative analyses, we selected two phosphorylation sites, Thr-225 and Ser-262, which have a higher abundance during senescence, and demonstrated that they play a key role in the function of ERD7 in regulating senescence. Transgenic plants overexpressing the phospho-mimetic mutant of the activation segment residues ERD7T225D and ERD7T262D exhibited a significantly early senescence, while the inactivation segment ERD7T225A and ERD7T262A displayed a delayed senescence. Moreover, we found that ERD7 regulates ROS accumulation by enhancing the expression of AtrbohD and AtrbohF, which is dependent on the critical residues, i.e., Thr-225 and Ser-262. Our findings suggest that ERD7 is a positive regulator of senescence, which might function as a crosstalk hub between age-dependent and stress-induced leaf senescence.
    Keywords:  Arabidopsis thaliana; ERD7; ROS; leaf senescence; phosphorylation
    DOI:  https://doi.org/10.3390/ijms25021328
  61. Front Immunol. 2023 ;14 1327852
    Glycolysis: an emerging regulator of osteoarthritis.
    Dingming Jiang, Jianan Guo, Yingquan Liu, Wenxin Li, Dezhao Lu.
      Osteoarthritis (OA) has been a leading cause of disability in the elderly and there remains a lack of effective therapeutic approaches as the mechanisms of pathogenesis and progression have yet to be elucidated. As OA progresses, cellular metabolic profiles and energy production are altered, and emerging metabolic reprogramming highlights the importance of specific metabolic pathways in disease progression. As a crucial part of glucose metabolism, glycolysis bridges metabolic and inflammatory dysfunctions. Moreover, the glycolytic pathway is involved in different areas of metabolism and inflammation, and is associated with a variety of transcription factors. To date, it has not been fully elucidated whether the changes in the glycolytic pathway and its associated key enzymes are associated with the onset or progression of OA. This review summarizes the important role of glycolysis in mediating cellular metabolic reprogramming in OA and its role in inducing tissue inflammation and injury, with the aim of providing further insights into its pathological functions and proposing new targets for the treatment of OA.
    Keywords:  glycolysis; immunometabolic reprogramming; inflammation; metabolism; osteoarthritis
    DOI:  https://doi.org/10.3389/fimmu.2023.1327852
  62. Front Immunol. 2023 ;14 1305933
    Immunological dimensions of neuroinflammation and microglial activation: exploring innovative immunomodulatory approaches to mitigate neuroinflammatory progression.
    Lucas Fornari Laurindo, Jefferson Aparecido Dias, Adriano Cressoni Araújo, Karina Torres Pomini, Cristiano Machado Galhardi, Claudia Rucco Penteado Detregiachi, Luíza Santos de Argollo Haber, Domingos Donizeti Roque, Marcelo Dib Bechara, Marcela Vialogo Marques de Castro, Eliana de Souza Bastos Mazuqueli Pereira, Ricardo José Tofano, Iris Jasmin Santos German Borgo, Sandra Maria Barbalho.
      The increasing life expectancy has led to a higher incidence of age-related neurodegenerative conditions. Within this framework, neuroinflammation emerges as a significant contributing factor. It involves the activation of microglia and astrocytes, leading to the release of pro-inflammatory cytokines and chemokines and the infiltration of peripheral leukocytes into the central nervous system (CNS). These instances result in neuronal damage and neurodegeneration through activated nucleotide-binding domain and leucine-rich repeat containing (NLR) family pyrin domain containing protein 3 (NLRP3) and nuclear factor kappa B (NF-kB) pathways and decreased nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Due to limited effectiveness regarding the inhibition of neuroinflammatory targets using conventional drugs, there is challenging growth in the search for innovative therapies for alleviating neuroinflammation in CNS diseases or even before their onset. Our results indicate that interventions focusing on Interleukin-Driven Immunomodulation, Chemokine (CXC) Receptor Signaling and Expression, Cold Exposure, and Fibrin-Targeted strategies significantly promise to mitigate neuroinflammatory processes. These approaches demonstrate potential anti-neuroinflammatory effects, addressing conditions such as Multiple Sclerosis, Experimental autoimmune encephalomyelitis, Parkinson's Disease, and Alzheimer's Disease. While the findings are promising, immunomodulatory therapies often face limitations due to Immune-Related Adverse Events. Therefore, the conduction of randomized clinical trials in this matter is mandatory, and will pave the way for a promising future in the development of new medicines with specific therapeutic targets.
    Keywords:  Alzheimer’s disease; immune system; microglia; microglial activation; neurodegenerative diseases; neuroimmunology; neuroinflammation; neuroinflammatory disorders
    DOI:  https://doi.org/10.3389/fimmu.2023.1305933
  63. J Vis Exp. 2024 Jan 05.
    Use of Minimally Invasive Methods to Assess Fuel Utilization and Circadian Rhythms in Older Adults.
    Christian McLaren, Carly Bohlman, Armin Ezzati, Karyn Esser, Christiaan Leeuwenburgh, Todd Manini, Marco Pahor, Stephen Anton, Stephanie E Wohlgemuth.
      Aging is associated with multiple physiological changes that contribute synergistically and independently to physical disability and the risk of chronic disease. Although the etiology of age-related physical disability is complex and multifactorial, the decline in mitochondrial function appears to coincide with the progression of functional decline in many older adults. The reason why there is a decrease in mitochondrial function with aging remains elusive, but emerging science indicates that both fuel metabolism and circadian rhythms can influence mitochondrial function. Recent studies have established that circadian rhythms become disturbed with aging, and that disrupted circadian rhythms have pathological consequences that impact mitochondrial function and overlap with many age-associated chronic diseases. Current quantitative methods for direct assessment of mitochondrial function are invasive and typically require a muscle biopsy, which can pose difficulties with participant recruitment and study adherence, given the perceived levels of potential pain and risk. Thus, an innovative and relatively noninvasive protocol to assess changes in mitochondrial function at the cellular level and circadian patterns in older adults was adapted. Specifically, a real-time metabolic flux analyzer is used to assess the mitochondrial bioenergetic function of white blood cells under differential substrate availability. The expression of circadian clock genes in white blood cells to cross-correlate with the mitochondrial bioenergetics and circadian rhythm outcomes are also analyzed. It is believed that these innovative methodological approaches will aid future clinical trials by providing minimally invasive methods for studying mitochondrial substrate preference and circadian rhythms in older adults.
    DOI:  https://doi.org/10.3791/64628
  64. bioRxiv. 2024 Jan 13. pii: 2024.01.12.575075. [Epub ahead of print]
    Mitochondrial membrane potential regulates nuclear DNA methylation and gene expression through phospholipid remodeling.
    Mateus Prates Mori, Oswaldo Lozoya, Ashley M Brooks, Dagoberto Grenet, Cristina A Nadalutti, Birgitta Ryback, Kai Ting Huang, Prottoy Hasan, Gyӧrgy Hajnóczky, Janine H Santos.
      Maintenance of the mitochondrial inner membrane potential (ΔΨM) is critical for many aspects of mitochondrial function, including mitochondrial protein import and ion homeostasis. While ΔΨM loss and its consequences are well studied, little is known about the effects of increased ΔΨM. In this study, we used cells deleted of ATPIF1 , a natural inhibitor of the hydrolytic activity of the ATP synthase, as a genetic model of mitochondrial hyperpolarization. Our data show that chronic ΔΨM increase leads to nuclear DNA hypermethylation, regulating transcription of mitochondria, carbohydrate and lipid metabolism genes. Surprisingly, remodeling of phospholipids, but not metabolites or redox changes, mechanistically links the ΔΨM to the epigenome. These changes were also observed upon chemical exposures and reversed by decreasing the ΔΨM, highlighting them as hallmark adaptations to chronic mitochondrial hyperpolarization. Our results reveal the ΔΨM as the upstream signal conveying the mitochondrial status to the epigenome to regulate cellular biology, providing a new framework for how mitochondria can influence health outcomes in the absence of canonical dysfunction.
    Highlights: Mitochondria hyperpolarization leads to nuclear DNA hypermethylationDNA methylation regulates expression of mitochondrial and lipid metabolism genesPhospholipid remodeling mediates the epigenetic effects of mitochondrial hyperpolarization.
    DOI:  https://doi.org/10.1101/2024.01.12.575075
  65. bioRxiv. 2024 Jan 04. pii: 2024.01.04.574228. [Epub ahead of print]
    Air pollution drives macrophage senescence through a phagolysosome-15-lipoxygenase pathway.
    Sarah A Thomas, Hwan Mee Yong, Ana M Rule, Naina Gour, Stephane Lajoie.
      Urban particulate matter (uPM) poses significant health risks, particularly to the respiratory system. Fine particles, such as PM 2.5 , can penetrate deep into the lungs and exacerbate a range of health problems, including emphysema, asthma, and lung cancer. PM exposure is also linked to extra-pulmonary disorders like heart and neurodegenerative diseases. Moreover, prolonged exposure to elevated PM levels can reduce overall life expectancy. Senescence is a dysfunctional cell state typically associated with age but can also be precipitated by environmental stressors. This study aimed to determine whether uPM could drive senescence in macrophages, an essential cell type involved in particulate phagocytosis-mediated clearance. While it is known that uPM exposure impairs immune function, this deficit is multi-faceted and incompletely understood, partly due to the use of particulates such as diesel exhaust particle (DEP) as a surrogate for true uPM. uPM was collected from several locations in the USA, including Baltimore, Houston, and Phoenix. Bone marrow-derived macrophages (BMDMs) were stimulated with uPM or reference particulates ( e.g., DEP) to assess senescence-related parameters. We report that uPM-exposed BMDMs adopt a senescent phenotype characterized by increased IL-1α secretion, senescence- associated β-galactosidase activity, and diminished proliferation. Exposure to allergens failed to elicit such a response, supporting a distinction between different types of environmental exposures. uPM-induced senescence was independent of key macrophage activation pathways, specifically inflammasome and scavenger receptor. However, inhibition of the phagolysosome pathway abrogated senescence markers, supporting this phenotype's attribution to uPM phagocytosis. These data suggest uPM exposure leads to macrophage senescence, which may contribute to immunopathology.
    DOI:  https://doi.org/10.1101/2024.01.04.574228
  66. bioRxiv. 2024 Jan 09. pii: 2024.01.09.574889. [Epub ahead of print]
    Experimental variables that impact outcomes in Caenorhabditis elegans aging stress response.
    Bradford Hull, Isabella M Irby, Kayla M Miller, Ally Anderson, Emily A Gardea, George L Sutphin.
      Cellular stress is a fundamental component of age-associated disease. Cells encounter various forms of stress - oxidative stress, protein misfolding, DNA damage, etc. - and respond by activating specific, well-defined stress response pathways. As we age, the burden of stress and resulting damage increases while our cells' ability to deal with the consequences becomes diminished due to dysregulation of cellular stress response pathways. Many interventions that extend lifespan activate one or more stress response pathways or allow cells to maintain normal stress response later in life. The nematode Caenorhabditis elegans is a commonly used model for both aging and stress response research. As such, stress response experiments are regularly conducted as part of studies focused on mechanisms of aging in C. elegans . However, experimental design across experiments in the field are highly variable, including stressor dose, age at exposure, culture type (liquid vs. solid), bacterial strain used as a food source, and environmental temperature. These differences can result in different experimental outcomes, making comparison of results between studies challenging. Here we evaluate several experimental variables that are variable in the published literature and find that each can meaningfully alter experimental outcomes for multiple stressors. Our goal is to raise awareness of the issue of experimental variability within the field and suggest a standardized experimental design to serve as a set of guidelines for future experiments. By adopting these guidelines as a starting point, and explicitly noting differences in specific experiments, we aim to promote rigor and reproducibility, ultimately fostering more interpretable and translatable outcomes in geroscience research.
    DOI:  https://doi.org/10.1101/2024.01.09.574889
  67. Front Microbiol. 2023 ;14 1320202
    Bazi Bushen capsule improves the deterioration of the intestinal barrier function by inhibiting NLRP3 inflammasome-mediated pyroptosis through microbiota-gut-brain axis.
    Shixiong Zhang, Mengnan Li, Liping Chang, Xinjing Mao, Yuning Jiang, Xiaogang Shen, Kunxu Niu, Xuan Lu, Runtao Zhang, Yahui Song, Kun Ma, Hongrong Li, Cong Wei, Yunlong Hou, Yiling Wu.
       Purpose: The senescence-accelerated prone mouse 8 (SAMP8) is a widely used model for accelerating aging, especially in central aging. Mounting evidence indicates that the microbiota-gut-brain axis may be involved in the pathogenesis and progression of central aging-related diseases. This study aims to investigate whether Bazi Bushen capsule (BZBS) attenuates the deterioration of the intestinal function in the central aging animal model.
    Methods: In our study, the SAMP8 mice were randomly divided into the model group, the BZ-low group (0.5 g/kg/d BZBS), the BZ-high group (1 g/kg/d BZBS) and the RAPA group (2 mg/kg/d rapamycin). Age-matched SAMR1 mice were used as the control group. Next, cognitive function was detected through Nissl staining and two-photon microscopy. The gut microbiota composition of fecal samples was analyzed by 16S rRNA gene sequencing. The Ileum tissue morphology was observed by hematoxylin and eosin staining, and the intestinal barrier function was observed by immunofluorescence. The expression of senescence-associated secretory phenotype (SASP) factors, including P53, TNF-α, NF-κB, IL-4, IL-6, and IL-10 was measured by real-time quantitative PCR. Macrophage infiltration and the proliferation and differentiation of intestinal cells were assessed by immunohistochemistry. We also detected the inflammasome and pyroptosis levels in ileum tissue by western blotting.
    Results: BZBS improved the cognitive function and neuronal density of SAMP8 mice. BZBS also restored the intestinal villus structure and barrier function, which were damaged in SAMP8 mice. BZBS reduced the expression of SASP factors and the infiltration of macrophages in the ileum tissues, indicating a lower level of inflammation. BZBS enhanced the proliferation and differentiation of intestinal cells, which are essential for maintaining intestinal homeostasis. BZBS modulated the gut microbiota composition, by which BZBS inhibited the activation of inflammasomes and pyroptosis in the intestine.
    Conclusion: BZBS could restore the dysbiosis of the gut microbiota and prevent the deterioration of intestinal barrier function by inhibiting NLRP3 inflammasome-mediated pyroptosis. These results suggested that BZBS attenuated the cognitive aging of SAMP8 mice, at least partially, by targeting the microbiota-gut-brain axis.
    Keywords:  SAMP8; inflammasome; intestinal barrier function; microbiota-gut-brain axis; pyroptosis
    DOI:  https://doi.org/10.3389/fmicb.2023.1320202
  68. Aging Dis. 2023 Nov 29.
    Telomeres: Dysfunction, Maintenance, Aging and Cancer.
    Pan Liao, Bo Yan, Conglin Wang, Ping Lei.
      Aging has emerged at the forefront of scientific research due to the growing social and economic costs associated with the growing aging global population. The defining features of aging involve a variety of molecular processes and cellular systems, which are interconnected and collaboratively contribute to the aging process. Herein, we analyze how telomere dysfunction potentially amplifies or accelerates the molecular and biochemical mechanisms underpinning each feature of aging and contributes to the emergence of age-associated illnesses, including cancer and neurodegeneration, via the perspective of telomere biology. Furthermore, the recently identified novel mechanistic actions for telomere maintenance offer a fresh viewpoint and approach to the management of telomeres and associated disorders. Telomeres and the defining features of aging are intimately related, which has implications for therapeutic and preventive approaches to slow aging and reduce the prevalence of age-related disorders.
    DOI:  https://doi.org/10.14336/AD.2023.1128
  69. Biomedicines. 2023 Dec 21. pii: 26. [Epub ahead of print]12(1):
    Cellular Senescence in Liver Cancer: How Dying Cells Become "Zombie" Enemies.
    Aurora Gazzillo, Camilla Volponi, Cristiana Soldani, Michela Anna Polidoro, Barbara Franceschini, Ana Lleo, Eduardo Bonavita, Matteo Donadon.
      Liver cancer represents the fourth leading cause of cancer-associated death worldwide. The heterogeneity of its tumor microenvironment (TME) is a major contributing factor of metastasis, relapse, and drug resistance. Regrettably, late diagnosis makes most liver cancer patients ineligible for surgery, and the frequent failure of non-surgical therapeutic options orientates clinical research to the investigation of new drugs. In this context, cellular senescence has been recently shown to play a pivotal role in the progression of chronic inflammatory liver diseases, ultimately leading to cancer. Moreover, the stem-like state triggered by senescence has been associated with the emergence of drug-resistant, aggressive tumor clones. In recent years, an increasing number of studies have emerged to investigate senescence-associated hepatocarcinogenesis and its derived therapies, leading to promising results. In this review, we intend to provide an overview of the recent evidence that unveils the role of cellular senescence in the most frequent forms of primary and metastatic liver cancer, focusing on the involvement of this mechanism in therapy resistance.
    Keywords:  cellular senescence; cholangiocarcinoma (CCA); colorectal liver mestastases (CLM); hepatocellular carcinoma (HCC); liver cancer; senescence-associated secretory phenotype; therapy resistance
    DOI:  https://doi.org/10.3390/biomedicines12010026
  70. Aging (Albany NY). 2024 Jan 22. 15
    The integration of multi-omics analysis and machine learning for the identification of prognostic assessment and immunotherapy efficacy through aging-associated genes in lung cancer.
    Wei Lu, Yun Zhou, Ruixuan Zhao, Qiushi Liu, Wei Yang, Tianyi Zhu.
       BACKGROUND: Recent years revealed key molecules in lung cancer research, yet their exact roles in disease onset and progression remain uncertain. Lung cancer's heterogeneity complicates prognosis prediction. This study integrates pivotal molecules to evaluate patient prognosis and immunotherapy efficacy.
    METHODS: The WGCNA algorithm identified module genes linked to immunity. The Lasso-Cox method built a prognostic model for outcome prediction. GO and KEGG analyses explored gene pathways. ssGSEA quantified immune cell types and functions. The riskScore predicts the effectiveness of immunotherapy based on its correlation with DNA repair and immune checkpoint genes. Single-cell sequencing examined key gene expression across cell types.
    RESULTS: Using WGCNA, we identified the MEbrown module related to immunity. Lasso-Cox selected "BLK," "ITGB4," "PRKCH," and "SNAI1" for the prognostic model. MF analysis revealed enriched functions including antigen binding, GTPase regulator activity. In terms of BP, processes like immune signaling and mitotic division were enriched. CC enrichment included immunoglobulin complexes and chromosomal regions. Enriched pathways encompassed Cell cycle, Focal adhesion, Cellular senescence, and p53 signaling. ssGSEA evaluated immune cell abundance. RiskScore correlated with CTLA4 and PD1 through MMR and immune checkpoint analysis. Single-cell analysis indicated gene expression across cell types for BLK, ITGB4, PRKCH, and SNAI1.
    CONCLUSION: In summary, our developed prognostic model utilizing age-related genes effectively predicts lung cancer prognosis and the efficacy of immune therapy.
    Keywords:  WGCNA; aging; immunotherapy; lung cancer; prognostic model
    DOI:  https://doi.org/10.18632/aging.205464
  71. Front Mol Neurosci. 2023 ;16 1329554
    Post-translational modification and mitochondrial function in Parkinson's disease.
    Shishi Luo, Danling Wang, Zhuohua Zhang.
      Parkinson's disease (PD) is the second most common neurodegenerative disease with currently no cure. Most PD cases are sporadic, and about 5-10% of PD cases present a monogenic inheritance pattern. Mutations in more than 20 genes are associated with genetic forms of PD. Mitochondrial dysfunction is considered a prominent player in PD pathogenesis. Post-translational modifications (PTMs) allow rapid switching of protein functions and therefore impact various cellular functions including those related to mitochondria. Among the PD-associated genes, Parkin, PINK1, and LRRK2 encode enzymes that directly involved in catalyzing PTM modifications of target proteins, while others like α-synuclein, FBXO7, HTRA2, VPS35, CHCHD2, and DJ-1, undergo substantial PTM modification, subsequently altering mitochondrial functions. Here, we summarize recent findings on major PTMs associated with PD-related proteins, as enzymes or substrates, that are shown to regulate important mitochondrial functions and discuss their involvement in PD pathogenesis. We will further highlight the significance of PTM-regulated mitochondrial functions in understanding PD etiology. Furthermore, we emphasize the potential for developing important biomarkers for PD through extensive research into PTMs.
    Keywords:  Parkinson’s disease; SUMOylation; acetylation; mitochondrial function; phosphorylation; post-translational modification (PTM); s-nitrosylation; ubiquitination
    DOI:  https://doi.org/10.3389/fnmol.2023.1329554
  72. iScience. 2024 Feb 16. 27(2): 108798
    A novel macrolide-Del-1 axis to regenerate bone in old age.
    Kridtapat Sirisereephap, Hikaru Tamura, Jong-Hyung Lim, Meircurius Dwi Condro Surboyo, Toshihito Isono, Takumi Hiyoshi, Andrea L Rosenkranz, Yurie Sato-Yamada, Hisanori Domon, Akari Ikeda, Tomoyasu Hirose, Toshiaki Sunazuka, Nagako Yoshiba, Hiroyuki Okada, Yutaka Terao, Takeyasu Maeda, Koichi Tabeta, Triantafyllos Chavakis, George Hajishengallis, Tomoki Maekawa.
      Aging is associated with increased susceptibility to chronic inflammatory bone loss disorders, such as periodontitis, in large part due to the impaired regenerative potential of aging tissues. DEL-1 exerts osteogenic activity and promotes bone regeneration. However, DEL-1 expression declines with age. Here we show that systemically administered macrolide antibiotics and a non-antibiotic erythromycin derivative, EM-523, restore DEL-1 expression in 18-month-old ("aged") mice while promoting regeneration of bone lost due to naturally occurring age-related periodontitis. These compounds failed to induce bone regeneration in age-matched DEL-1-deficient mice. Consequently, these drugs promoted DEL-1-dependent functions, including alkaline phosphatase activity and osteogenic gene expression in the periodontal tissue while inhibiting osteoclastogenesis, leading to net bone growth. Macrolide-treated aged mice exhibited increased skeletal bone mass, suggesting that this treatment may be pertinent to systemic bone loss disorders. In conclusion, we identified a macrolide-DEL-1 axis that can regenerate bone lost due to aging-related disease.
    Keywords:  Age; Immunology; Small molecule
    DOI:  https://doi.org/10.1016/j.isci.2024.108798
  73. Chin Med J (Engl). 2024 Jan 26.
    Disulfiram: A novel repurposed drug for cancer therapy.
    Min Zeng, Baibei Wu, Wenjie Wei, Zihan Jiang, Peiqiang Li, Yuanting Quan, Xiaobo Hu.
       ABSTRACT: Cancer is a major global health issue. Effective therapeutic strategies can prolong patients' survival and reduce the costs of treatment. Drug repurposing, which identifies new therapeutic uses for approved drugs, is a promising approach with the advantages of reducing research costs, shortening development time, and increasing efficiency and safety. Disulfiram (DSF), an Food and Drug Administration (FDA)-approved drug used to treat chronic alcoholism, has a great potential as an anticancer drug by targeting diverse human malignancies. Several studies show the antitumor effects of DSF, particularly the combination of DSF and copper (DSF/Cu), on a wide range of cancers such as glioblastoma (GBM), breast cancer, liver cancer, pancreatic cancer, and melanoma. In this review, we summarize the antitumor mechanisms of DSF/Cu, including induction of intracellular reactive oxygen species (ROS) and various cell death signaling pathways, and inhibition of proteasome activity, as well as inhibition of nuclear factor-kappa B (NF-κB) signaling. Furthermore, we highlight the ability of DSF/Cu to target cancer stem cells (CSCs), which provides a new approach to prevent tumor recurrence and metastasis. Strikingly, DSF/Cu inhibits several molecular targets associated with drug resistance, and therefore it is becoming a novel option to increase the sensitivity of chemo-resistant and radio-resistant patients. Studies of DSF/Cu may shed light on its improved application to clinical tumor treatment.
    DOI:  https://doi.org/10.1097/CM9.0000000000002909
  74. J Exp Zool A Ecol Integr Physiol. 2024 Jan 22.
    The association between age and telomere length is age-dependent: Evidence for a threshold model of telomere length maintenance.
    Ana Á Romero-Haro, Ellis Mulder, Mark F Haussmann, Barbara Tschirren.
      Telomere length and dynamics are commonly used biomarkers of somatic state, yet the role of telomeres underlying the aging process is still debated. Indeed, to date, empirical evidence for an association between age and telomere length is mixed. Here, we test if the age-dependency of the association between age and telomere length can provide a potential explanation for the reported inconsistencies across studies. To this end, we quantified telomere length by telomere restriction fragment analysis in two groups of Japanese quail (Coturnix japonica) that differed in their age distribution. One group consisted of young adults only, whereas the second group consisted of adults across a wide range of ages. In the young adults group, there was a highly significant negative association between telomere length and age, whereas no association between age and telomere length was found in the all-ages adults group. This difference between groups was not due to telomere length-dependent selective disappearance. Our results shows that the association between telomere length and age is age-dependent and suggest that the costs and benefits associated with telomere maintenance are dynamic across an individual's life course.
    Keywords:  ageing; evolutionary theory of ageing; evolutionary trade-offs; life-history strategies; telomere shortening and attrition
    DOI:  https://doi.org/10.1002/jez.2785
  75. Molecules. 2024 Jan 15. pii: 419. [Epub ahead of print]29(2):
    6-Shogaol Ameliorates Liver Inflammation and Fibrosis in Mice on a Methionine- and Choline-Deficient Diet by Inhibiting Oxidative Stress, Cell Death, and Endoplasmic Reticulum Stress.
    Ah Young Yang, Kiryeong Kim, Hyun Hee Kwon, Jaechan Leem, Jeong Eun Song.
      Non-alcoholic steatohepatitis (NASH) is becoming an increasingly serious global health threat, distinguished by hepatic lipid accumulation, inflammation, and fibrosis. There is a lack of approved pharmaceutical interventions for this disease, highlighting the urgent need for effective treatment. This study explores the hepatoprotective potential of 6-shogaol, a natural compound derived from ginger, in a methionine- and choline-deficient (MCD) dietary mouse model of NASH. Male C57BL/6J mice were subjected to the MCD diet for 4 weeks to induce NASH, with concurrent intraperitoneal administration of 6-shogaol (20 mg/kg) three times a week. While 6-shogaol did not impact body weight, liver weight, or hepatic lipid accumulation, it effectively mitigated liver injury, inflammation, and fibrosis in MCD diet-fed mice. Mechanistically, 6-shogaol inhibited lipid and DNA oxidation, restored hepatic glutathione levels, and regulated the expression of pro-oxidant and antioxidant enzymes. Furthermore, 6-shogaol inhibited apoptosis and necroptosis, as indicated by a decrease in TUNEL-stained cells and downregulation of apoptosis- and necroptosis-associated proteins. Additionally, 6-shogaol alleviated endoplasmic reticulum (ER) stress, as demonstrated by decreased expression of molecules associated with unfolded protein response pathways. These findings underscore the potential of 6-shogaol as a therapeutic intervention for NASH by targeting pathways related to oxidative stress, cell death, and ER stress.
    Keywords:  6-shogaol; fibrosis; inflammation; non-alcoholic steatohepatitis
    DOI:  https://doi.org/10.3390/molecules29020419
  76. Comb Chem High Throughput Screen. 2024 Jan 18.
    Nuclear Factor Kappa B: A Nobel Therapeutic Target of Flavonoids Against Parkinson's Disease.
    Niraj Kumar Singh, Ashini Singh, Mayank.
      Parkinson's disease (PD), the most common brain-related neurodegenerative disorder, is comprised of several pathophysiological mechanisms, such as mitochondrial dysfunction, neuroinflammation, aggregation of misfolded alpha-synuclein, and synaptic loss in the substantia nigra pars compacta region of the midbrain. Misfolded alpha-synuclein, originating from damaged neurons, triggers a series of signaling pathways in both glial and neuronal cells. Activation of such events results in the production and expression of several proinflammatory cytokines via the activation of the nuclear factor κB (NF-κB) signaling pathway. Consequently, this cascade of events worsens the neurodegenerative processes, particularly in conditions, such as PD and synucleinopathies. Microglia, astrocytes, and neurons are just a few of the many cells and tissues that express the NF-κB family of inducible types of transcription factors. The dual role of NF-κB activation can be crucial for neuronal survival, although the classical NF-κB pathway is important for controlling the generation of inflammatory mediators during neuroinflammation. Modulating NF-κB-associated pathways through the selective action of several agents holds promise for mitigating dopaminergic neuronal degeneration and PD. Several naturally occurring compounds in medicinal plants can be an effective treatment option in attenuating PD-associated dopaminergic neuronal loss via selectively modifying the NF-κB-mediated signaling pathways. Recently, flavonoids have gained notable attention from researchers because of their remarkable anti-neuroinflammatory activity and significant antioxidant properties in numerous neurodegenerative disorders, including PD. Several subclasses of flavonoids, including flavones, flavonols, isoflavones, and anthocyanins, have been evaluated for neuroprotective effects against in vitro and in vivo models of PD. In this aspect, the present review highlights the pathological role of NF-κB in the progression of PD and investigates the therapeutic potential of natural flavonoids targeting the NF-κB signaling pathway for the prevention and management of PD-like manifestations with a comprehensive list for further reference. Available facts strongly support that bioactive flavonoids could be considered in food and/or as lead pharmacophores for the treatment of neuroinflammation-mediated PD. Furthermore, natural flavonoids having potent pharmacological properties could be helpful in enhancing the economy of countries that cultivate medicinal plants yielding bioactive flavonoids on a large scale.
    Keywords:  Flavonoid; NF-κB; Neuroinflammation; Neuroprotection; Parkinson's disease
    DOI:  https://doi.org/10.2174/0113862073295568240105025006
  77. Int J Mol Sci. 2024 Jan 09. pii: 821. [Epub ahead of print]25(2):
    Nrf2 Pathway and Oxidative Stress as a Common Target for Treatment of Diabetes and Its Comorbidities.
    Michelle Yi, Leslie Cruz Cisneros, Eric J Cho, Michael Alexander, Francesca A Kimelman, Lourdes Swentek, Antoney Ferrey, Ekamol Tantisattamo, Hirohito Ichii.
      Diabetes is a chronic disease that induces many comorbidities, including cardiovascular disease, nephropathy, and liver damage. Many mechanisms have been suggested as to how diabetes leads to these comorbidities, of which increased oxidative stress in diabetic patients has been strongly implicated. Limited knowledge of antioxidative antidiabetic drugs and substances that can address diabetic comorbidities through the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway calls for detailed investigation. This review will describe how diabetes increases oxidative stress, the general impact of that oxidative stress, and how oxidative stress primarily contributes to diabetic comorbidities. It will also address how treatments for diabetes, especially focusing on their effects on the Nrf2 antioxidative pathway, have been shown to similarly affect the Nrf2 pathway of the heart, kidney, and liver systems. This review demonstrates that the Nrf2 pathway is a common pathogenic component of diabetes and its associated comorbidities, potentially identifying this pathway as a target to guide future treatments.
    Keywords:  Nrf2; diabetes; heart; kidney; liver; oxidative stress
    DOI:  https://doi.org/10.3390/ijms25020821
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