bims-caglex Biomed News
on Cellular aging and life extension
Issue of 2024–01–07
fifty-two papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño
  1. Microphysiological systems for human aging research.
  2. The influence of the gut microbiome on ovarian aging.
  3. Pharmacological targeting of senescence with senolytics as a new therapeutic strategy for neurodegeneration.
  4. 3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights into MFN-2 Mediated Changes.
  5. Human trials exploring anti-aging medicines.
  6. YTHDC1 delays cellular senescence and pulmonary fibrosis by activating ATR in an m6A-independent manner.
  7. Titan mice as a model to test interventions that attenuate frailty and increase longevity.
  8. Mitochondrial genome editing: strategies, challenges, and applications.
  9. Cell-type specific molecular signatures of aging revealed in a brain-wide transcriptomic cell-type atlas.
  10. Flavonoid 4,4'-dimethoxychalcone selectively eliminates senescent cells via activating ferritinophagy.
  11. SerpinA3N regulates the secretory phenotype of mouse senescent astrocytes contributing to neurodegeneration.
  12. Tackling cognitive decline in late adulthood: Cognitive interventions.
  13. Rhythmic musical activities may strengthen connectivity between brain networks associated with aging-related deficits in timing and executive functions.
  14. Irradiation-induced hair graying in mice: an experimental model to evaluate the effectiveness of interventions targeting oxidative stress, DNA damage prevention, and cellular senescence.
  15. Canthaxanthin Attenuates the Vascular Aging or Endothelial Cell Senescence by Inhibiting Inflammation and Oxidative Stress in Mice.
  16. Activation of senescence in critically ill patients: mechanisms, consequences and therapeutic opportunities.
  17. Vitamin K: New insights related to senescence and cancer metastasis.
  18. Imbalance of synaptic and extrasynaptic NMDA receptors induced by the deletion of CRMP1 accelerates age-related cognitive decline in mice.
  19. Association Between Hippocampal Volumes and Cognition in Cerebral Amyloid Angiopathy.
  20. Composite dietary antioxidant index associated with delayed biological aging: a population-based study.
  21. Derailed protein turnover in the aging mammalian brain.
  22. The crosstalk between telomeres and DNA repair mechanisms: an overview to mammalian somatic cells, germ cells, and preimplantation embryos.
  23. Chrysin alleviates DNA damage to improve disturbed immune homeostasis and pro-angiogenic environment in laser-induced choroidal neovascularization.
  24. Amount and intensity of physical activity and risk of incident cancer in the UK Biobank.
  25. Simple and Highly Specific Targeting of Resident Microglia with Adeno-Associated Virus.
  26. Update on the Use of Pulse Wave Velocity to Measure Age-Related Vascular Changes.
  27. Moderate dietary restriction delays the onset of age-associated sarcopenia in Caenorhabditis elegans due to reduced myosin UNC-54 degradation.
  28. Drawing as an efficient encoding tool in younger but not always older adults: The case of associative memory.
  29. Polygenic prediction of human longevity on the supposition of pervasive pleiotropy.
  30. The ubiquitin-conjugating enzyme UBE2D/eff maintains a youthful proteome and ensures protein quality control during aging.
  31. Liquid biopsy in ovarian cancer in China and the world: current status and future perspectives.
  32. The role of inflammasomes in human diseases and their potential as therapeutic targets.
  33. Inflammasomes as regulators of mechano-immunity.
  34. Yeast EndoG prevents genome instability by degrading cytoplasmic DNA.
  35. Assessing causal associations between neurodegenerative diseases and neurological tumors with biological aging: a bidirectional Mendelian randomization study.
  36. Machine learning models for blood pressure phenotypes combining multiple polygenic risk scores.
  37. Alterations in neuromuscular junction morphology with ageing and endurance training modulate neuromuscular transmission and myofibre composition.
  38. Perspectives on anemia: Factors confounding understanding of past occurrence.
  39. Role of astrocyte senescence regulated by the non- canonical autophagy in the neuroinflammation associated to cerebral malaria.
  40. Cell Tree Rings: the structure of somatic evolution as a human aging timer.
  41. Mangiferin attenuates osteoporosis by inhibiting osteoblastic ferroptosis through Keap1/Nrf2/SLC7A11/GPX4 pathway.
  42. Aging disrupts spatiotemporal regulation of germline stem cells and niche integrity.
  43. Lactoferrin ameliorated obesity-induced endothelial dysfunction by inhibiting the Tak1/IL-18/eNOS pathway between PVAT and vascular endothelium.
  44. Using focused ultrasound to modulate microglial structure and function.
  45. Phosphomimetic substitutions in TDP-43's transiently α-helical region suppress phase separation.
  46. Screens in aging-relevant human ALS-motor neurons identify MAP4Ks as therapeutic targets for the disease.
  47. Paracrine cross-talk between human adipose tissue-derived endothelial cells and perivascular cells accelerates the endothelialization of an electrospun ionomeric polyurethane scaffold.
  48. Mechanisms of Immune Sensing of DNA Damage.
  49. Chronic Administration of 13-cis-retinoic Acid Induces Depression-Like Behavior by Altering the Activity of Dentate Granule Cells.
  50. Synovial Tissue Insights into Heterogeneity of Rheumatoid Arthritis.
  51. An ATM D-compartmentalization in DNA damage response.
  52. N6-methyladenosine in myeloid cells: a novel regulatory factor for inflammation-related diseases.
  1. Aging Cell. 2024 Jan 05. e14070
    Microphysiological systems for human aging research.
    Seungman Park, Thomas C Laskow, Jingchun Chen, Prasun Guha, Buddhadeb Dawn, Deok-Ho Kim.
      Recent advances in microphysiological systems (MPS), also known as organs-on-a-chip (OoC), enable the recapitulation of more complex organ and tissue functions on a smaller scale in vitro. MPS therefore provide the potential to better understand human diseases and physiology. To date, numerous MPS platforms have been developed for various tissues and organs, including the heart, liver, kidney, blood vessels, muscle, and adipose tissue. However, only a few studies have explored using MPS platforms to unravel the effects of aging on human physiology and the pathogenesis of age-related diseases. Age is one of the risk factors for many diseases, and enormous interest has been devoted to aging research. As such, a human MPS aging model could provide a more predictive tool to understand the molecular and cellular mechanisms underlying human aging and age-related diseases. These models can also be used to evaluate preclinical drugs for age-related diseases and translate them into clinical settings. Here, we provide a review on the application of MPS in aging research. First, we offer an overview of the molecular, cellular, and physiological changes with age in several tissues or organs. Next, we discuss previous aging models and the current state of MPS for studying human aging and age-related conditions. Lastly, we address the limitations of current MPS and present future directions on the potential of MPS platforms for human aging research.
    Keywords:  age-related changes; age-related diseases; aging; aging phenotypes; microphysiological systems
    DOI:  https://doi.org/10.1111/acel.14070
  2. Gut Microbes. 2024 Jan-Dec;16(1):16(1): 2295394
    The influence of the gut microbiome on ovarian aging.
    Feiling Huang, Ying Cao, Jinghui Liang, Ruiyi Tang, Si Wu, Peng Zhang, Rong Chen.
      Ovarian aging occurs prior to the aging of other organ systems and acts as the pacemaker of the aging process of multiple organs. As life expectancy has increased, preventing ovarian aging has become an essential goal for promoting extended reproductive function and improving bone and genitourinary conditions related to ovarian aging in women. An improved understanding of ovarian aging may ultimately provide tools for the prediction and mitigation of this process. Recent studies have suggested a connection between ovarian aging and the gut microbiota, and alterations in the composition and functional profile of the gut microbiota have profound consequences on ovarian function. The interaction between the gut microbiota and the ovaries is bidirectional. In this review, we examine current knowledge on ovary-gut microbiota crosstalk and further discuss the potential role of gut microbiota in anti-aging interventions. Microbiota-based manipulation is an appealing approach that may offer new therapeutic strategies to delay or reverse ovarian aging.
    Keywords:  Ovarian aging; anti-ovarian aging; fecal microbiota transplantation; gut microbiome; menopause; premature ovarian insufficiency
    DOI:  https://doi.org/10.1080/19490976.2023.2295394
  3. Mol Pharmacol. 2023 Dec 08. pii: MOLPHARM-MR-2023-000803. [Epub ahead of print]
    Pharmacological targeting of senescence with senolytics as a new therapeutic strategy for neurodegeneration.
    Miriam Richardson, Des R Richardson.
      Cellular senescence is a state of permanent cell cycle arrest. Early in life, senescence has a physiological role in tumor suppression and wound healing. However, gradually, as these senescent cells accumulate over the lifespan of an organism, they contribute to inflammation and the progression of age-related diseases, including neurodegeneration. Targeting senescent cells using a class of drugs known as "senolytics" holds great promise for the management of Alzheimer's and Parkinson's disease. Already, several senolytic compounds have been shown to ameliorate cognitive deficits across several preclinical models of neurodegeneration. Most of these senolytics (e.g., dasatinib) are repurposed clinical or experimental anti-cancer drugs, which trigger apoptosis of senescent cells by interfering with pro-survival pathways. However, outside of their senolytic function, many first-generation senolytics also have other less appreciated neuroprotective effects such as potent antioxidant and anti-inflammatory activity. While these corollary properties of senolytics could be beneficial, in some cases, the effects may lead to negative dose-limiting toxicities, including thrombocytopenia. In this review, we discuss the various biological pathways targeted by the leading senolytic drugs, namely dasatinib, quercetin, fisetin, and navitoclax. We further evaluate the clinical transability of these compounds for neurodegeneration, assessing their adverse effects, pharmacokinetic properties, and chemical structure. Significance Statement Currently, there are no effective disease-modifying treatments for the most prevalent neurodegenerative disorders, including Alzheimer's and Parkinson's disease. In addition, some of the drugs that are currently available for these diseases are associated with unwanted side-effects and/or become less efficacious with time. Therefore, researchers have begun to explore new innovative treatments for these belligerent diseases, including senolytic drugs. These agents lead to the apoptosis of senescent cells thereby preventing their deleterious role in neurodegeneration.
    Keywords:  drug targeting; molecular drug targeting
    DOI:  https://doi.org/10.1124/molpharm.123.000803
  4. bioRxiv. 2023 Dec 14. pii: 2023.11.13.566502. [Epub ahead of print]
    3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights into MFN-2 Mediated Changes.
    Estevão Scudese, Zer Vue, Prassana Katti, Andrea Marshall, Larry Vang, Edgar Garza López, Kit Neikirk, Dominique Stephens, Duane D Hall, Rahmati Rostami, Jian-Qiang Shao, Margaret Mungai, Salma T AshShareef, Innes Hicsasmaz, Sasha Manus, Celestine Wanjalla, Aaron Whiteside, Clintoria Williams, Steven M Damo, Jennifer A Gaddy, Annet Kirabo, Brian Glancy, Estélio Henrique Martin Dantas, André Kinder, Fabiana Scartoni, Matheus Baffi, Melanie R McReynolds, Mark A Phillips, Anthonya Cooper, Sandra A Murray, Vernat Exil, Bret C Mobley, Antentor Hinton.
      Sarcopenia is an age-related loss of skeletal muscle, characterized by loss of mass, strength, endurance, and oxidative capacity during aging. Notably, bioenergetics and protein turnover studies have shown that mitochondria mediate this decline in function. Although mitochondrial aging is associated with decreased mitochondrial capacity, the three-dimensional (3D) mitochondrial structure associated with morphological changes in skeletal muscle during aging still requires further elucidation. Although exercise has been the only therapy to mitigate sarcopenia, the mechanisms that govern these changes remain unclear. We hypothesized that aging causes structural remodeling of mitochondrial 3D architecture representative of dysfunction, and this effect is mitigated by exercise. We used serial block-face scanning electron microscopy to image human skeletal tissue samples, followed by manual contour tracing using Amira software for 3D reconstruction and subsequent analysis of mitochondria. We then applied a rigorous in vitro and in vivo exercise regimen during aging. We found that mitochondria became less complex with age. Specifically, mitochondria lost surface area, complexity, and perimeter, indicating age-related declines in ATP synthesis and interaction capacity. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age-related losses. Exercise stimulation restored mitofusin 2 (MFN2), which we show is required for mitochondrial structure. Furthermore, we show that this pathway is evolutionarily conserved with Marf, the MFN2 ortholog in Drosophila , as Marf knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. Our results define age-related structural changes in mitochondria and further suggest that exercise may mitigate age-related structural decline through modulation of mitofusins.
    DOI:  https://doi.org/10.1101/2023.11.13.566502
  5. Cell Metab. 2023 Dec 22. pii: S1550-4131(23)00458-8. [Epub ahead of print]
    Human trials exploring anti-aging medicines.
    Leonard Guarente, David A Sinclair, Guido Kroemer.
      Here, we summarize the current knowledge on eight promising drugs and natural compounds that have been tested in the clinic: metformin, NAD+ precursors, glucagon-like peptide-1 receptor agonists, TORC1 inhibitors, spermidine, senolytics, probiotics, and anti-inflammatories. Multiple clinical trials have commenced to evaluate the efficacy of such agents against age-associated diseases including diabetes, cardiovascular disease, cancer, and neurodegenerative diseases. There are reasonable expectations that drugs able to decelerate or reverse aging processes will also exert broad disease-preventing or -attenuating effects. Hence, the outcome of past, ongoing, and future disease-specific trials may pave the way to the development of new anti-aging medicines. Drugs approved for specific disease indications may subsequently be repurposed for the treatment of organism-wide aging consequences.
    Keywords:  age-related disease; autophagy; metformin; nicotinamide mononucleotide/NAD(+)/sirtuins; senescence
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.007
  6. EMBO J. 2024 Jan;43(1): 61-86
    YTHDC1 delays cellular senescence and pulmonary fibrosis by activating ATR in an m6A-independent manner.
    Canfeng Zhang, Liping Chen, Chen Xie, Fengwei Wang, Juan Wang, Haoxian Zhou, Qianyi Liu, Zhuo Zeng, Na Li, Junjiu Huang, Yong Zhao, Haiying Liu.
      Accumulation of DNA damage in the lung induces cellular senescence and promotes age-related diseases such as idiopathic pulmonary fibrosis (IPF). Hence, understanding the mechanistic regulation of DNA damage repair is important for anti-aging therapies and disease control. Here, we identified an m6A-independent role of the RNA-binding protein YTHDC1 in counteracting stress-induced pulmonary senescence and fibrosis. YTHDC1 is primarily expressed in pulmonary alveolar epithelial type 2 (AECII) cells and its AECII expression is significantly decreased in AECIIs during fibrosis. Exogenous overexpression of YTHDC1 alleviates pulmonary senescence and fibrosis independent of its m6A-binding ability, while YTHDC1 deletion enhances disease progression in mice. Mechanistically, YTHDC1 promotes the interaction between TopBP1 and MRE11, thereby activating ATR and facilitating DNA damage repair. These findings reveal a noncanonical function of YTHDC1 in delaying cellular senescence, and suggest that enhancing YTHDC1 expression in the lung could be an effective treatment strategy for pulmonary fibrosis.
    Keywords:  ATR; IPF; Senescence; YTHDC1
    DOI:  https://doi.org/10.1038/s44318-023-00003-2
  7. Geroscience. 2024 Jan 05.
    Titan mice as a model to test interventions that attenuate frailty and increase longevity.
    Benedikt Gille, Annika Müller-Eigner, Shari Gottschalk, Erika Wytrwat, Martina Langhammer, Shahaf Peleg.
      Wild-type murine models for aging research have lifespans of several years, which results in long experimental duration and late output. Here we explore the short-lived non-inbred Titan mouse (DU6) as a mouse model to test longevity interventions. We show that Titan mice exhibit increased frailty and senescence-associated beta-galactosidase activity at an early age. Dietary intervention attenuates the frailty progression of Titan mice. Additionally, cyclic administration of the senolytic drug Navitoclax at an early age increases the lifespan and reduces senescence-associated beta-galactosidase activity. Our data suggests that Titan mice can serve as a cost-effective and timely model for longevity interventions in mammals.
    Keywords:  Aging; Dietary intervention; Frailty index; Mouse models; Navitoclax
    DOI:  https://doi.org/10.1007/s11357-023-01045-4
  8. BMB Rep. 2024 Jan 05. pii: 6125. [Epub ahead of print]
    Mitochondrial genome editing: strategies, challenges, and applications.
    Kayeong Lim.
      Mitochondrial DNA (mtDNA), a multicopy genome found in mitochondria, is crucial for oxidative phosphorylation. Mutations in mtDNA can lead to severe mitochondrial dysfunction in tissues and organs with high energy demand. MtDNA mutations are closely associated with mitochondrial and age-related disease. To better understand the functional role of mtDNA and work toward developing therapeutics, it is essential to advance technology that is capable of manipulating the mitochondrial genome. This review discusses ongoing efforts in mitochondrial genome editing with mtDNA nucleases and base editors, including the tools, delivery strategies, and applications. Future advances in mitochondrial genome editing to address challenges regarding their efficiency and specificity can achieve the promise of therapeutic genome editing.
  9. bioRxiv. 2023 Jul 27. pii: 2023.07.26.550355. [Epub ahead of print]
    Cell-type specific molecular signatures of aging revealed in a brain-wide transcriptomic cell-type atlas.
    Kelly Jin, Zizhen Yao, Cindy T J van Velthoven, Eitan S Kaplan, Katie Glattfelder, Samuel T Barlow, Gabriella Boyer, Daniel Carey, Tamara Casper, Anish Bhaswanth Chakka, Rushil Chakrabarty, Michael Clark, Max Departee, Marie Desierto, Amanda Gary, Jessica Gloe, Jeff Goldy, Nathan Guilford, Junitta Guzman, Daniel Hirschstein, Changkyu Lee, Elizabeth Liang, Trangthanh Pham, Melissa Reding, Kara Ronellenfitch, Augustin Ruiz, Josh Sevigny, Nadiya Shapovalova, Lyudmila Shulga, Josef Sulc, Amy Torkelson, Herman Tung, Boaz Levi, Susan M Sunkin, Nick Dee, Luke Esposito, Kimberly Smith, Bosiljka Tasic, Hongkui Zeng.
      Biological aging can be defined as a gradual loss of homeostasis across various aspects of molecular and cellular function. Aging is a complex and dynamic process which influences distinct cell types in a myriad of ways. The cellular architecture of the mammalian brain is heterogeneous and diverse, making it challenging to identify precise areas and cell types of the brain that are more susceptible to aging than others. Here, we present a high-resolution single-cell RNA sequencing dataset containing ∼1.2 million high-quality single-cell transcriptomic profiles of brain cells from young adult and aged mice across both sexes, including areas spanning the forebrain, midbrain, and hindbrain. We find age-associated gene expression signatures across nearly all 130+ neuronal and non-neuronal cell subclasses we identified. We detect the greatest gene expression changes in non-neuronal cell types, suggesting that different cell types in the brain vary in their susceptibility to aging. We identify specific, age-enriched clusters within specific glial, vascular, and immune cell types from both cortical and subcortical regions of the brain, and specific gene expression changes associated with cell senescence, inflammation, decrease in new myelination, and decreased vasculature integrity. We also identify genes with expression changes across multiple cell subclasses, pointing to certain mechanisms of aging that may occur across wide regions or broad cell types of the brain. Finally, we discover the greatest gene expression changes in cell types localized to the third ventricle of the hypothalamus, including tanycytes, ependymal cells, and Tbx3 + neurons found in the arcuate nucleus that are part of the neuronal circuits regulating food intake and energy homeostasis. These findings suggest that the area surrounding the third ventricle in the hypothalamus may be a hub for aging in the mouse brain. Overall, we reveal a dynamic landscape of cell-type-specific transcriptomic changes in the brain associated with normal aging that will serve as a foundation for the investigation of functional changes in the aging process and the interaction of aging and diseases.
    DOI:  https://doi.org/10.1101/2023.07.26.550355
  10. Redox Biol. 2023 Dec 30. pii: S2213-2317(23)00418-4. [Epub ahead of print]69 103017
    Flavonoid 4,4'-dimethoxychalcone selectively eliminates senescent cells via activating ferritinophagy.
    Tianxiang Wang, Changmei Yang, Zhiqiang Li, Ting Li, Ran Zhang, Yujiao Zhao, Tianyi Cheng, Zhaoyun Zong, Yingying Ma, Dongyuan Zhang, Haiteng Deng.
      Flavonoids are bioactive natural polyphenolic compounds with health benefits, including anti-tumor, anti-inflammatory and anti-aging effects. Our previous studies revealed that a flavonoid 4,4'-dimethoxychalcone (DMC) induced ferroptosis via inhibiting ferrochelatase (FECH). However, the effect of DMC on cellular senescence is unknown. In the present study, we found that DMC treatment selectively eliminated senescent cells, and DMC alone or a combination of DMC and quercetin or dasatinib showed high efficiency in the clearance of senescent cells. We identified FECH was highly expressed in senescent cells compared to non-senescent cells. Mechanistically, we found that DMC inhibited FECH and induced ferritinophagy, which led to an increase of labile iron pool, triggering ferroptosis of senescent cells. Importantly, we found that DMC treatment prevented hair loss, improved motor coordination, and reduced the expression of several senescence-associated secretory phenotype factors (IL-6, IL-1β, CXCL-10, and MMP12) in the liver of old mice. Collectively, we revealed that, through the induction of ferroptosis, DMC holds the promise as a new senolytics to prevent age-related pathologies.
    Keywords:  4,4′-dimethoxychalcone; FECH; Ferritinophagy; Ferroptosis; Senescence; Senolytics
    DOI:  https://doi.org/10.1016/j.redox.2023.103017
  11. J Gerontol A Biol Sci Med Sci. 2024 Jan 04. pii: glad278. [Epub ahead of print]
    SerpinA3N regulates the secretory phenotype of mouse senescent astrocytes contributing to neurodegeneration.
    Xiaojuan Han, Qing Lei, Huanhuan Liu, Tianying Zhang, Xingchun Gou.
      Senescent astrocyte accumulation in the brain during normal aging is a driver of age-related neurodegenerative diseases such as Alzheimer's disease (AD). However, the molecular events underlying astrocyte senescence in AD are not fully understood. In this study, we demonstrated that senescent astrocytes display a secretory phenotype known as the senescence-associated secretory phenotype (SASP), which is associated with the upregulation of various proinflammatory factors and the downregulation of neurotrophic growth factors (e.g., NGF and BDNF), resulting in a decrease in astrocyte-mediated neuroprotection and increased risk of neurodegeneration. We found that SerpinA3N is upregulated in senescent primary mouse astrocytes after serial passaging in vitro or by H2O2 treatment. Further exploration of the underlying mechanism revealed that SerpinA3N deficiency protects against senescent astrocyte-induced neurodegeneration by suppressing SASP-related factors and inducing neurotrophic growth factors. Brain tissues from AD model mice possessed increased numbers of senescent astrocytes. Moreover, senescent astrocytes exhibited upregulated SerpinA3N expression in vitro and in vivo, confirming that our cell model recapitulated the in vivo pathology of these neurodegenerative diseases. Altogether, our study reveals a novel molecular strategy to regulate the secretory phenotype of senescent astrocytes and implies that SerpinA3N and its regulatory mechanisms may be potential targets for delaying brain aging and aging-related neurodegenerative diseases.
    Keywords:  SerpinA3N; astrocytes senescence; neurodegeneration; senescence-associated secretory phenotype
    DOI:  https://doi.org/10.1093/gerona/glad278
  12. Curr Opin Psychol. 2023 Dec 07. pii: S2352-250X(23)00225-7. [Epub ahead of print]56 101780
    Tackling cognitive decline in late adulthood: Cognitive interventions.
    Claudia C von Bastian, Eleanor R A Hyde, Shuangke Jiang.
      Affordable and easy-to-administer interventions such as cognitive training, cognitively stimulating everyday leisure activities, and non-invasive brain stimulation techniques, are promising avenues to counteract age-related cognitive decline and support people in maintaining cognitive health into late adulthood. However, the same pattern of findings emerges across all three fields of cognitive intervention research: whereas improvements within the intervention context are large and often reliable, generalisation to other cognitive abilities and contexts are severely limited. These findings suggest that while cognitive interventions can enhance the efficiency with which people use their existing cognitive capacity, these interventions are unlikely to expand existing capacity limits. Therefore, future research investigating generalisation of enhanced efficiency constitutes a promising avenue for developing reliably effective cognitive interventions.
    Keywords:  Cognitive aging; Cognitive training; Lifestyle engagement; Non-invasive brain stimulation
    DOI:  https://doi.org/10.1016/j.copsyc.2023.101780
  13. Exp Gerontol. 2024 Jan 02. pii: S0531-5565(23)00275-9. [Epub ahead of print] 112354
    Rhythmic musical activities may strengthen connectivity between brain networks associated with aging-related deficits in timing and executive functions.
    Aaron Colverson, Stephanie Barsoum, Ronald Cohen, John Williamson.
      Brain aging and common conditions of aging (e.g., hypertension) affect networks important in organizing information, processing speed and action programming (i.e., executive functions). Declines in these networks may affect timing and could have an impact on the ability to perceive and perform musical rhythms. There is evidence that participation in rhythmic musical activities may help to maintain and even improve executive functioning (near transfer), perhaps due to similarities in brain regions underlying timing, musical rhythm perception and production, and executive functioning. Rhythmic musical activities may present as a novel and fun activity for older adults to stimulate interacting brain regions that deteriorate with aging. However, relatively little is known about neurobehavioral interactions between aging, timing, rhythm perception and production, and executive functioning. In this review, we account for these brain-behavior interactions to suggest that deeper knowledge of overlapping brain regions associated with timing, rhythm, and cognition may assist in designing more targeted preventive and rehabilitative interventions to reduce age-related cognitive decline and improve quality of life in populations with neurodegenerative disease. Further research is needed to elucidate the functional relationships between brain regions associated with aging, timing, rhythm perception and production, and executive functioning to direct design of targeted interventions.
    Keywords:  Aging; Executive functioning; Rhythm perception and production; Timing
    DOI:  https://doi.org/10.1016/j.exger.2023.112354
  14. Geroscience. 2024 Jan 06.
    Irradiation-induced hair graying in mice: an experimental model to evaluate the effectiveness of interventions targeting oxidative stress, DNA damage prevention, and cellular senescence.
    Anna Ungvari, Tamas Kiss, Rafal Gulej, Stefano Tarantini, Boglarka Csik, Andriy Yabluchanskiy, Peter Mukli, Anna Csiszar, Melissa L Harris, Zoltan Ungvari.
      Hair graying, also known as canities or achromotrichia, is a natural phenomenon associated with aging and is influenced by external factors such as stress, environmental toxicants, and radiation exposure. Understanding the mechanisms underlying hair graying is an ideal approach for developing interventions to prevent or reverse age-related changes in regenerative tissues. Hair graying induced by ionizing radiation (γ-rays or X-rays) has emerged as a valuable experimental model to investigate the molecular pathways involved in this process. In this review, we examine the existing evidence on radiation-induced hair graying, with a particular focus on the potential role of radiation-induced cellular senescence. We explore the current understanding of hair graying in aging, delve into the underlying mechanisms, and highlight the unique advantages of using ionizing-irradiation-induced hair graying as a research model. By elucidating the molecular pathways involved, we aim to deepen our understanding of hair graying and potentially identify novel therapeutic targets to address this age-related phenotypic change.
    Keywords:  Achromotrichia; Aging; Canities; Hair graying; Senescence; Skin
    DOI:  https://doi.org/10.1007/s11357-023-01042-7
  15. Front Biosci (Landmark Ed). 2023 Dec 29. 28(12): 367
    Canthaxanthin Attenuates the Vascular Aging or Endothelial Cell Senescence by Inhibiting Inflammation and Oxidative Stress in Mice.
    Zhefeng Wang, Lilin Li, Souqi Liao, Ren Huang, Yibo Jiang, Jia Fei, Lijun Cai, Keda Zhang.
       BACKGROUND: Vascular endothelial dysfunction is an early phenotype of aging-related vascular dysfunction. Delaying vascular aging and preventing cardiovascular disease are major public health problems that urgently need to be solved. Scientists have studied various drugs to prevent the occurrence and progress of cardiovascular disease, but progress has been slow. Here, the antisenescence and anti-endothelial damage of canthaxanthin (CX, which is an active molecule from food) has been studied.
    METHODS: This study was performed by adding CX to a model of cell senescence and oxidative damage induced by hydrogen peroxide. Cellular senescence markers (e.g., p16, p21, and p53) and oxidative damage markers (e.g., reactive oxygen species, nitric oxide, malondialdehyde, superoxide dismutase) were evaluated by the enzyme-linked immunosorbent assay, laser scanning confocal microscopy, and Western blotting.
    RESULTS: We found that CX downregulated the expression level of senescence-associated molecules, and significantly reduced the oxidative damage of vascular endothelial cells. These observations showed that CX effectively alleviated the senescence of vascular endothelial cells. Furthermore, CX treatment reduced the expression levels of interleukin-6 (IL-6), tumor necrosis factor alpha, and IL-1β. Finally, in vivo, CX significantly alleviated vascular senescence.
    CONCLUSIONS: The current study shows that CX has potential application value for treating vascular aging or endothelial cell senescence.
    Keywords:  Canthaxanthin; oxidative damage; senescence; vascular endothelial cells
    DOI:  https://doi.org/10.31083/j.fbl2812367
  16. Ann Intensive Care. 2024 Jan 05. 14(1): 2
    Activation of senescence in critically ill patients: mechanisms, consequences and therapeutic opportunities.
    Paula Martín-Vicente, Cecilia López-Martínez, Beatriz Rioseras, Guillermo M Albaiceta.
      Whereas aging is a whole-organism process, senescence is a cell mechanism that can be triggered by several stimuli. There is increasing evidence that critical conditions activate cell senescence programs irrespective of patient's age. In this review, we briefly describe the basic senescence pathways and the consequences of their activation in critically ill patients. The available evidence suggests a paradigm in which activation of senescence can be beneficial in the short term by rendering cells resistant to apoptosis, but also detrimental in a late phase by inducing a pro-inflammatory and pro-fibrotic state. Senescence can be a therapeutic target. The use of drugs that eliminate senescent cells (senolytics) or the senescence-associated phenotype (senomorphics) will require monitoring of these cell responses and identification of therapeutic windows to improve the outcome of critically ill patients.
    Keywords:  Apoptosis; DNA damage response; Post-ICU syndrome; Senescence; Senotherapeutics
    DOI:  https://doi.org/10.1186/s13613-023-01236-4
  17. Biochim Biophys Acta Rev Cancer. 2023 Dec 27. pii: S0304-419X(23)00206-8. [Epub ahead of print] 189057
    Vitamin K: New insights related to senescence and cancer metastasis.
    Anqi Chen, Jialu Li, Nianxuan Shen, Haifeng Huang, Qinglei Hang.
      Several clinical trials and experimental studies have recently shown that vitamin K (VK) supplementation benefits the human body. Specifically, VK participates in coagulation and is associated with cellular senescence and cancer. VK has a potential anticancer effect in various cancers, such as pancreatic and prostate cancers. Through anti-inflammatory and antioxidant effects, VK can prevent senescence and inhibit cancer metastasis. Therefore, cancer prognosis can be improved by preventing cellular senescence. In addition, VK can inhibit the proliferation, growth, and differentiation of cancer cells through various mechanisms, including induction of c-myc and c-fos genes, regulation of B-cell lymphoma-2 (Bcl-2) and p21 genes, and angiogenesis inhibition. This review aims to discuss the relationship among VK, cellular senescence, and cancer metastasis and thus may improve comprehension of the specific function of VK in human health. The potential application of VK as an adjuvant therapy for cancer (or in combination with traditional chemotherapy drugs or other vitamins) has also been highlighted.
    Keywords:  Cancer metastasis; Cellular senescence; Inflammation; Oxidative stress; Vitamin K
    DOI:  https://doi.org/10.1016/j.bbcan.2023.189057
  18. Neurobiol Aging. 2023 Dec 29. pii: S0197-4580(23)00304-4. [Epub ahead of print]135 48-59
    Imbalance of synaptic and extrasynaptic NMDA receptors induced by the deletion of CRMP1 accelerates age-related cognitive decline in mice.
    Yun-Chieh Tsai, Sheng-Min Huang, Hsu-Hsia Peng, Shu-Wha Lin, Shu-Rung Lin, Ting-Yu Chin, Shih-Ming Huang.
      Collapsin response mediator protein 1 (CRMP1) is involved in semaphorin 3A signaling pathway, promoting neurite extension and growth cone collapse. It is highly expressed in the nervous system, especially the hippocampus. The crmp1 knockout (KO) mice display impaired spatial learning and memory, and this phenomenon seemingly tends to deteriorate with age. Here we investigated whether CRMP1 is involved in age-related cognitive decline in WT and crmp1 KO mice at adult, middle-aged and older stages. The results revealed that cognitive dysfunction in the Morris water maze task became more severe and decreased glutamate and glutamine level in middle-aged crmp1 KO mice. Additionally, increasing levels of extrasynaptic NMDA receptors and phosphorylation of Tau were observed in middle-aged crmp1 KO mice, leading to synaptic and neuronal loss in the CA3 regions of hippocampus. These findings suggest that deletion of CRMP1 accelerates age-related cognitive decline by disrupting the balance between synaptic and extrasynaptic NMDA receptors, resulting in the loss of synapses and neurons.
    Keywords:  Age-related cognitive decline; CRMP1; Extrasynaptic NMDA receptor; Phosphorylated Tau; Synaptic NMDA receptor
    DOI:  https://doi.org/10.1016/j.neurobiolaging.2023.12.006
  19. Neurology. 2024 Jan 23. 102(2): e207854
    Association Between Hippocampal Volumes and Cognition in Cerebral Amyloid Angiopathy.
    Valentina Perosa, Maria Clara Zanon Zotin, Dorothee Schoemaker, Lukas Sveikata, Mark R Etherton, Andreas Charidimou, Steven M Greenberg, Anand Viswanathan.
       BACKGROUND AND OBJECTIVES: Accumulating evidence suggests that gray matter atrophy, often considered a marker of Alzheimer disease (AD), can also result from cerebral small vessel disease (CSVD). Cerebral amyloid angiopathy (CAA) is a form of sporadic CSVD, diagnosed through neuroimaging criteria, that often co-occurs with AD pathology and leads to cognitive impairment. We sought to identify the role of hippocampal integrity in the development of cognitive impairment in a cohort of patients with possible and probable CAA.
    METHODS: Patients were recruited from an ongoing CAA study at Massachusetts General Hospital. Composite scores defined performance in the cognitive domains of memory, language, executive function, and processing speed. Hippocampal subfields' volumes were measured from 3T MRI, using an automated method, and multivariate linear regression models were used to estimate their association with each cognitive domain and relationship to CAA-related neuroimaging markers.
    RESULTS: One hundred twenty patients, 36 with possible (age mean [range]: 75.6 [65.6-88.9]), 67 with probable CAA (75.9 [59.0-94.0]), and 17 controls without cognitive impairment and CSVD (72.4 [62.5-82.7]; 76.4% female patients), were included in this study. We found a positive association between all investigated hippocampal subfields and memory and language, whereas specific subfields accounted for executive function (CA4 [Estimate = 5.43; 95% CI 1.26-9.61; p = 0.020], subiculum [Estimate = 2.85; 95% CI 0.67-5.02; p = 0.022]), and processing speed (subiculum [Estimate = 1.99; 95% CI 0.13-3.85; p = 0.036]). These findings were independent of other CAA-related markers, which did not have an influence on cognition in this cohort. Peak width of skeletonized mean diffusivity (PSMD), a measure of white matter integrity, was negatively associated with hippocampal subfields' volumes (CA3 [Estimate = -0.012; 95% CI -0.020 to -0.004; p = 0.034], CA4 [Estimate = -0.010; 95% CI -0.020 to -0.0007; p = 0.037], subiculum [Estimate = -0.019; 95% CI -0.042 to -0.0001; p = 0.003]).
    DISCUSSION: These results suggest that hippocampal integrity is an independent contributor to cognitive impairment in patients with CAA and that it might be related to loss of integrity in the white matter. Further studies exploring potential causes and directionality of the relationship between white matter and hippocampal integrity may be warranted.
    DOI:  https://doi.org/10.1212/WNL.0000000000207854
  20. Aging (Albany NY). 2024 Jan 02. 15
    Composite dietary antioxidant index associated with delayed biological aging: a population-based study.
    Huiqin He, Xin Chen, Yiming Ding, Xiaoli Chen, Xingkang He.
       OBJECTIVE: The objective of this study was to explore the potential correlation between the composite dietary antioxidant index (CDAI) and biological aging, addressing the insufficient epidemiological evidence in this area.
    METHODS: Participants meeting eligibility criteria were selected from the National Health and Nutrition Examination Surveys (NHANES) conducted between 2001 and 2018. CDAI was determined based on dietary antioxidants obtained from 24-hour dietary recalls. Biological age was determined using PhenoAge algorithms incorporating various clinical features. Weighted multiple models were employed to investigate and assess the association between CDAI and biological age.
    RESULTS: Analysis of the CDAI quartile revealed disparities in terms of age, gender, ethnicity, educational level, marital status, poverty, dietary calories intakes, smoking, drinking status, BMI, physical activity, and PhenoAge. After adjusting for potential confounding factors, a significant inverse relationship was found between CDAI and Phenotypic Age, with each standard deviation increase in CDAI score correlating with a 0.18-year decrease in Phenotypic Age. These negative correlations between CDAI and PhenoAge advancement were observed regardless of age, gender, physical activity status, smoking status, and body mass index.
    CONCLUSIONS: Our findings demonstrate a positive relationship between higher CDAI scores and delayed biological aging. These results have significant implications for public health initiatives aimed at promoting healthy aging through dietary interventions.
    Keywords:  PhenoAge; aging; composite dietary antioxidant index; national health and nutrition examination surveys
    DOI:  https://doi.org/10.18632/aging.205232
  21. Mol Syst Biol. 2024 Jan 05.
    Derailed protein turnover in the aging mammalian brain.
    Nalini R Rao, Arun Upadhyay, Jeffrey N Savas.
      Efficient protein turnover is essential for cellular homeostasis and organ function. Loss of proteostasis is a hallmark of aging culminating in severe dysfunction of protein turnover. To investigate protein turnover dynamics as a function of age, we performed continuous in vivo metabolic stable isotope labeling in mice along the aging continuum. First, we discovered that the brain proteome uniquely undergoes dynamic turnover fluctuations during aging compared to heart and liver tissue. Second, trends in protein turnover in the brain proteome during aging showed sex-specific differences that were tightly tied to cellular compartments. Next, parallel analyses of the insoluble proteome revealed that several cellular compartments experience hampered turnover, in part due to misfolding. Finally, we found that age-associated fluctuations in proteasome activity were associated with the turnover of core proteolytic subunits, which was recapitulated by pharmacological suppression of proteasome activity. Taken together, our study provides a proteome-wide atlas of protein turnover across the aging continuum and reveals a link between the turnover of individual proteasome subunits and the age-associated decline in proteasome activity.
    Keywords:  Aging; proteasome; protein turnover; quantitative proteomics; stable isotope labeling
    DOI:  https://doi.org/10.1038/s44320-023-00009-2
  22. J Assist Reprod Genet. 2024 Jan 02.
    The crosstalk between telomeres and DNA repair mechanisms: an overview to mammalian somatic cells, germ cells, and preimplantation embryos.
    Betul Tire, Gunel Talibova, Saffet Ozturk.
      Telomeres are located at the ends of linear chromosomes and play a critical role in maintaining genomic stability by preventing premature activation of DNA repair mechanisms. Because of exposure to various genotoxic agents, telomeres can undergo shortening and genetic changes. In mammalian cells, the basic DNA repair mechanisms, including base excision repair, nucleotide excision repair, double-strand break repair, and mismatch repair, function in repairing potential damages in telomeres. If these damages are not repaired correctly in time, the unfavorable results such as apoptosis, cell cycle arrest, and cancerous transition may occur. During lifespan, mammalian somatic cells, male and female germ cells, and preimplantation embryos experience a number of telomeric damages. Herein, we comprehensively reviewed the crosstalk between telomeres and the DNA repair mechanisms in the somatic cells, germ cells, and embryos. Infertility development resulting from possible defects in this crosstalk is also discussed in the light of existing studies.
    Keywords:  DNA damages in telomeres; DNA repair mechanisms; Embryos; Infertility; Oocytes; Spermatogenic cells
    DOI:  https://doi.org/10.1007/s10815-023-03008-2
  23. Biochim Biophys Acta Mol Cell Res. 2024 Jan 02. pii: S0167-4889(23)00230-6. [Epub ahead of print] 119657
    Chrysin alleviates DNA damage to improve disturbed immune homeostasis and pro-angiogenic environment in laser-induced choroidal neovascularization.
    Jing Wang, Zilin Wang, Jingshu Liu, Minwen Zhou, Hong Wang, Hong Zhu, Mei Jiang, Qiyu Bo, Xiaodong Sun.
      Choroidal neovascularization (CNV) is a devastating pathology of numerous ocular diseases, such as wet age-related macular degeneration (wAMD), which causes irreversible vision loss. Although anti-vascular endothelial growth factor (VEGF) therapy has been widely used, poor response or no response still exists in some cases, suggesting that there are other components involved in the angiogenic process. Therefore, the underlying mechanism needs to be clarified and new target of anti-angiogenic therapy is urgently needed. It has been demonstrated that damaged retinal pigment epithelium (RPE) cells can activate inflammasome, driving a degenerative tissue environment and an enhanced pro-angiogenic response, which implies that RPE dysfunction may be a hallmark of the pathogenesis. Previously, we have shown that DNA damage can induce RPE dysfunction, triggering senescence-associated secretory phenotype (SASP) and local inflammation. In this study, we identify that chrysin can reduce DNA damage, especially telomere erosion in vitro, thus compromise the dysfunction of RPE and the decreased expression of SASP factor. Importantly, we find that DNA damage of RPE cells is remarkable in laser-induced CNV lesion, resulting in inflammatory response, which can be ameliorated by chrysin, mainly through IL-17 signaling pathway and its downstream signal transducer and activator of transcription 3 (STAT3) activities. In summary, our results indicate the interplay between DNA damage, perturbed RPE homeostasis, inflammatory response and angiogenesis in laser-induced CNV, and more importantly, chrysin may be an effective therapeutic supplement for CNV.
    Keywords:  Angiogenesis; Choroidal neovascularization; Chrysin; DNA damage; Inflammation; RPE dysfunction
    DOI:  https://doi.org/10.1016/j.bbamcr.2023.119657
  24. medRxiv. 2023 Dec 04. pii: 2023.12.04.23299386. [Epub ahead of print]
    Amount and intensity of physical activity and risk of incident cancer in the UK Biobank.
    Alaina H Shreves, Scott R Small, Rosemary Walmsley, Shing Chan, Pedro F Saint-Maurice, Steven C Moore, Keren Papier, Kezia Gaitskell, Ruth C Travis, Charles E Matthews, Aiden Doherty.
       Importance: The influence of total daily and light intensity activity on cancer risk remains unclear, as most existing knowledge is drawn from studies relying on self-reported leisure-time activities of moderate-vigorous intensity.
    Objective: To investigate associations between total daily activity, including step counts, and activity intensity on incident cancer risk.
    Design Setting and Participants: Prospective analysis of cancer-free UK Biobank participants who wore accelerometers for 7-days (between 2013-2015), followed for cancer incidence through national registries (mean follow-up 5.8 years (SD=1.3)).
    Exposures: Time-series machine learning models derived daily total activity (average acceleration), behaviour time, step counts, and peak 30-minute cadence from wrist-based accelerometer data.
    Main Outcomes and Measures: A composite cancer outcome of 13 cancers previously associated with low physical activity (bladder, breast, colon, endometrial, oesophageal adenocarcinoma, gastric cardia, head and neck, kidney, liver, lung, myeloid leukaemia, myeloma, and rectum) based on previous studies of self-reported activity. Cox proportional hazards regression models estimated hazard ratios (HR) and 95% confidence intervals (CI), adjusted for age, sex, ethnicity, smoking, alcohol, education, Townsend Deprivation Index, and reproductive factors. Associations of reducing sedentary time in favour of increased light and moderate-vigorous activity were examined using compositional data analyses.
    Results: Among 86 556 participants (mean age 62.0 years (SD=7.9) at accelerometer assessment), 2 669 cancers occurred. Higher total physical activity was associated with a lower overall cancer risk (HR 1SD =0.85, [95%CI 0.81-0.89]). On average, reallocating one hour/day from sedentary behaviour to moderate-vigorous physical activity was associated with a lower risk (HR=0.92, [0.89-0.95]), as was reallocating one hour/day to light-intensity physical activity (HR=0.94, [0.92-0.96]). Compared to individuals taking 5 000 daily steps, those who took 9 000 steps had an 18% lower risk of physical-activity-related cancer (HR=0.82, [0.74-0.90]). We found no significant association with peak 30-minute cadence after adjusting for total steps.
    Conclusion and Relevance: Higher total daily physical activity and less sedentary time, in favour of both light and moderate-vigorous intensity activity, were associated with a lower risk of certain cancers. For less active adults, increasing step counts by 4 000 daily steps may be a practical public health intervention for lowering the risk of some cancers.
    KEY POINTS: Question: What insights can we gain about the relationships between total daily activity, step counts, and activity intensity on cancer risk using accelerometer data?Findings: In an analysis of 86 556 individuals from the UK Biobank who provided a week of accelerometer-based activity data, higher levels of total physical activity, reducing sedentary time in favour of light or moderate-vigorous intensity activities, and higher daily step counts were associated with a lower risk of certain cancers.Meaning: For less active adults, increasing activity time and accumulating more daily steps may be practical interventions for lowering the risk of some cancers.
    DOI:  https://doi.org/10.1101/2023.12.04.23299386
  25. bioRxiv. 2023 Dec 13. pii: 2023.12.12.571321. [Epub ahead of print]
    Simple and Highly Specific Targeting of Resident Microglia with Adeno-Associated Virus.
    Carolina Serrano, Sergio Cananzi, Tianjin Shen, Lei-Lei Wang, Chun-Li Zhang.
      Microglia, as the immune cells of the central nervous system (CNS), play dynamic roles in both health and diseased conditions. The ability to genetically target microglia using viruses is crucial for understanding their functions and advancing microglia-based treatments. We here show that resident microglia can be simply and specifically targeted using adeno-associated virus (AAV) vectors containing a 466-bp DNA fragment from the human IBA1 ( hIBA1 ) promoter. This targeting approach is applicable to both resting and reactive microglia. When combining the short hIBA1 promoter with the target sequence of miR124, up to 95% of transduced cells are identified as microglia. Such a simple and highly specific microglia-targeting strategy may be further optimized for research and therapeutics.
    Significance Statement: Brain microglia play critical roles in human health and diseases. Genetic manipulation of these cells will offer numerous therapeutic opportunities. However, there is a lack of relevant strategies to target these cells with high specificity since they are traditionally considered to be refractory to virus transduction. Through in vivo screening of many promoters, this study identified a short promoter from the human IBA1 gene. When incorporated into lentivirus or adeno-associated virus vectors, this promoter proves effective in driving gene expression with high specificity for brain microglia. Such a simple strategy will facilitate specific approaches for microglia-based research.
    DOI:  https://doi.org/10.1101/2023.12.12.571321
  26. Curr Hypertens Rep. 2023 Dec 30.
    Update on the Use of Pulse Wave Velocity to Measure Age-Related Vascular Changes.
    Andrea G Marshall, Kit Neikirk, Jeremiah Afolabi, Naome Mwesigwa, Bryanna Shao, Annet Kirabo, Anilkumar K Reddy, Antentor Hinton.
       PURPOSE OF REVIEW: Pulse wave velocity (PWV) is an important and well-established measure of arterial stiffness that is strongly associated with aging. Age-related alterations in the elastic properties and integrity of arterial walls can lead to cardiovascular disease. PWV measurements play an important role in the early detection of these changes, as well as other cardiovascular disease risk factors, such as hypertension. This review provides a comprehensive summary of the current knowledge of the effects of aging on arterial stiffness, as measured by PWV.
    RECENT FINDINGS: This review highlights recent findings showing the applicability of PWV analysis for investigating heart failure, hypertension, and other cardiovascular diseases, as well as cerebrovascular diseases and Alzheimer's disease. It also discusses the clinical implications of utilizing PWV to monitor treatment outcomes, various challenges in implementing PWV assessment in clinical practice, and the development of new technologies, including machine learning and artificial intelligence, which may improve the usefulness of PWV measurements in the future. Measuring arterial stiffness through PWV remains an important technique to study aging, especially as the technology continues to evolve. There is a clear need to leverage PWV to identify interventions that mitigate age-related increases in PWV, potentially improving CVD outcomes and promoting healthy vascular aging.
    Keywords:  Arterial stiffness; Cardiovascular disease; Physiology; Pulse wave velocity; Therapies; Vascular
    DOI:  https://doi.org/10.1007/s11906-023-01285-x
  27. Mech Ageing Dev. 2023 Dec 30. pii: S0047-6374(23)00126-4. [Epub ahead of print] 111900
    Moderate dietary restriction delays the onset of age-associated sarcopenia in Caenorhabditis elegans due to reduced myosin UNC-54 degradation.
    Sobha Tumbapo, Adam Strudwick, Jana J Stastna, Simon C Harvey, Marieke J Bloemink.
      Sarcopenia, a gradual decrease in skeletal muscle mass and strength, is a major component of frailty in the elderly, with age, (lack of) exercise and diet found to be the major risk factors. The nematode Caenorhabditis elegans is an important model of sarcopenia. Although many studies describe loss of muscle function in ageing C. elegans, surprisingly few report on the loss of muscle mass. Here, in order to quantify loss of muscle mass under various dietary restriction (DR) conditions, we used an internal GFP standard to determine levels of the major body wall muscle myosin (UNC-54) in transgenic unc-54::gfp worms over their lifespan. Myosin density linearly increased during the first week of adulthood and there was no significant effect of DR. In contrast, an exponential decrease in myosin density was seen during the second week of adulthood, with reduced rates of myosin loss for mild and medium DR compared to control. UNC-54 turnover rates, previously determined using pulse-labelling methods, correspond well with the t1/2 value found here for UNC-54-GFP using fluorescence (control t1/2 = 12.0 days), independently validating our approach. These data indicate that sarcopenia is delayed in worms under mild and medium DR due to a reduced rate of myosin UNC-54 degradation, thereby maintaining protein homeostasis.
    Keywords:  Aging; C. elegans; healthspan; myosin UNC-54; sarcopenia
    DOI:  https://doi.org/10.1016/j.mad.2023.111900
  28. Mem Cognit. 2024 Jan 04.
    Drawing as an efficient encoding tool in younger but not always older adults: The case of associative memory.
    Rebecca Ovalle-Fresa, Corinna S Martarelli.
      Episodic memory strongly declines in healthy aging, at least partly because of reduced abilities to create and remember associations (associative memory) and to use efficient memory strategies. Several studies have shown that drawing the to-be-remembered material is a reliable encoding tool to enhance memory of individual items (item memory) because it simultaneously integrates elaborative, pictorial, and motoric processes. These processes in isolation can enhance associative memory in older adults. Nevertheless, their simultaneous impact on associative memory has never been investigated in drawing as an encoding tool. We aimed to investigate whether drawing as an encoding tool not only enhances item memory, but whether its benefit extends to associative memory in younger and older adults. Therefore, we tested 101 older and 100 younger participants in two online experiments and one in-person experiment. Using a memory task for unrelated word-pairs, we compared relational drawing and repeatedly writing (non-relational) as encoding tools and assessed immediate recognition memory of items and associations. In Experiment 2, we additionally assessed recognition memory after 1 week. The findings were consistent across the three experiments: while younger participants benefited from drawing over writing in item and associative memory, older participants benefited in item but not in associative memory. The observed effects remained after 1 week. Thus, we could extend the benefit of drawing to relational drawing in associative memory in younger adults. The lack of benefit in older adults' associative memory might be explained by age-related difficulties in benefiting from memory strategies, and in creating and retrieving associations.
    Keywords:  Aging; Associative memory; Drawing; Episodic memory; Strategy
    DOI:  https://doi.org/10.3758/s13421-023-01503-6
  29. medRxiv. 2023 Dec 11. pii: 2023.12.10.23299795. [Epub ahead of print]
    Polygenic prediction of human longevity on the supposition of pervasive pleiotropy.
    M Reza Jabalameli, Jhih-Rong Lin, Quanwei Zhang, Zhen Wang, Joydeep Mitra, Nha Nguyen, Tina Gao, Mark Khusidman, Gil Atzmon, Sofiya Milman, Jan Vijg, Nir Barzilai, Zhengdong D Zhang.
      The highly polygenic nature of human longevity renders cross-trait pleiotropy an indispensable feature of its genetic architecture. Leveraging the genetic correlation between the aging-related traits (ARTs), we sought to model the additive variance in lifespan as a function of cumulative liability from pleiotropic segregating variants. We tracked allele frequency changes as a function of viability across different age bins and prioritized 34 variants with an immediate implication on lipid metabolism, body mass index (BMI), and cognitive performance, among other traits, revealed by PheWAS analysis in the UK Biobank. Given the highly complex and non-linear interactions between the genetic determinants of longevity, we reasoned that a composite polygenic score would approximate a substantial portion of the variance in lifespan and developed the integrated longevity genetic scores ( iLGSs ) for distinguishing exceptional survival. We showed that coefficients derived from our ensemble model could potentially reveal an interesting pattern of genomic pleiotropy specific to lifespan. We assessed the predictive performance of our model for distinguishing the enrichment of exceptional longevity among long-lived individuals in two replication cohorts and showed that the median lifespan in the highest decile of our composite prognostic index is up to 4.8 years longer. Finally, using the proteomic correlates of iLGS , we identified protein markers associated with exceptional longevity irrespective of chronological age and prioritized drugs with repurposing potentials for gerotherapeutics. Together, our approach demonstrates a promising framework for polygenic modeling of additive liability conferred by ARTs in defining exceptional longevity and assisting the identification of individuals at higher risk of mortality for targeted lifestyle modifications earlier in life. Furthermore, the proteomic signature associated with iLGS highlights the functional pathway upstream of the PI3K-Akt that can be effectively targeted to slow down aging and extend lifespan.
    DOI:  https://doi.org/10.1101/2023.12.10.23299795
  30. bioRxiv. 2023 Dec 13. pii: 2023.12.12.571303. [Epub ahead of print]
    The ubiquitin-conjugating enzyme UBE2D/eff maintains a youthful proteome and ensures protein quality control during aging.
    Liam C Hunt, Kudzai Nyamkondiwa, Anna Stephan, Jianqin Jiao, Kanisha Kavdia, Vishwajeeth Pagala, Junmin Peng, Fabio Demontis.
      Ubiquitin-conjugating enzymes (E2s) are key for regulating protein function and turnover via ubiquitination but it remains undetermined which E2s maintain proteostasis during aging. Here, we find that E2s have diverse roles in handling a model aggregation-prone protein (huntingtin-polyQ) in the Drosophila retina: while some E2s mediate aggregate assembly, UBE2D/effete (eff) and other E2s are required for huntingtin-polyQ degradation. UBE2D/eff is key for proteostasis also in skeletal muscle: eff protein levels decline with aging, and muscle-specific eff knockdown causes an accelerated buildup in insoluble poly-ubiquitinated proteins (which progressively accumulate with aging) and shortens lifespan. Transgenic expression of human UBE2D2, homologous to eff, partially rescues the lifespan and proteostasis deficits caused by muscle-specific eff RNAi by re-establishing the physiological levels of eff RNAi -regulated proteins. Interestingly, UBE2D/eff knockdown in young age reproduces many of the proteomic changes that normally occur in old muscles, suggesting that the decrease in UBE2D/eff protein levels that occurs with aging contributes to reshaping the composition of the muscle proteome. Altogether, these findings indicate that UBE2D/eff is a key E2 ubiquitin-conjugating enzyme for maintaining a youthful proteome and for ensuring protein quality control during aging.
    DOI:  https://doi.org/10.1101/2023.12.12.571303
  31. Front Oncol. 2023 ;13 1276085
    Liquid biopsy in ovarian cancer in China and the world: current status and future perspectives.
    Hui Zhang, Lingxia Wang, Huanwen Wu.
      Ovarian cancer (OC) is the eighth most common cancer in women, but the mild, non-specific clinical presentation in early stages often prevents diagnosis until progression to advanced-stage disease, contributing to the high mortality associated with OC. While serum cancer antigen 125 (CA-125) has been successfully used as a blood-borne marker and is routinely monitored in patients with OC, CA-125 testing has limitations in sensitivity and specificity and does not provide direct information on important molecular characteristics that can guide treatment decisions, such as homologous recombination repair deficiency. We comprehensively review the literature surrounding methods based on liquid biopsies, which may provide improvements in sensitivity, specificity, and provide valuable additional information to enable early diagnosis, monitoring of recurrence/progression/therapeutic response, and accurate prognostication for patients with OC, highlighting applications of this research in China.
    Keywords:  China; cell-free DNA; circulating tumor DNA; liquid biopsy; ovarian cancer; poly(ADP)ribose polymerase inhibitors
    DOI:  https://doi.org/10.3389/fonc.2023.1276085
  32. Signal Transduct Target Ther. 2024 Jan 05. 9(1): 10
    The role of inflammasomes in human diseases and their potential as therapeutic targets.
    Jing Yao, Keenan Sterling, Zhe Wang, Yun Zhang, Weihong Song.
      Inflammasomes are large protein complexes that play a major role in sensing inflammatory signals and triggering the innate immune response. Each inflammasome complex has three major components: an upstream sensor molecule that is connected to a downstream effector protein such as caspase-1 through the adapter protein ASC. Inflammasome formation typically occurs in response to infectious agents or cellular damage. The active inflammasome then triggers caspase-1 activation, followed by the secretion of pro-inflammatory cytokines and pyroptotic cell death. Aberrant inflammasome activation and activity contribute to the development of diabetes, cancer, and several cardiovascular and neurodegenerative disorders. As a result, recent research has increasingly focused on investigating the mechanisms that regulate inflammasome assembly and activation, as well as the potential of targeting inflammasomes to treat various diseases. Multiple clinical trials are currently underway to evaluate the therapeutic potential of several distinct inflammasome-targeting therapies. Therefore, understanding how different inflammasomes contribute to disease pathology may have significant implications for developing novel therapeutic strategies. In this article, we provide a summary of the biological and pathological roles of inflammasomes in health and disease. We also highlight key evidence that suggests targeting inflammasomes could be a novel strategy for developing new disease-modifying therapies that may be effective in several conditions.
    DOI:  https://doi.org/10.1038/s41392-023-01687-y
  33. EMBO Rep. 2023 Dec 15.
    Inflammasomes as regulators of mechano-immunity.
    Jelena S Bezbradica, Clare E Bryant.
      Mechano-immunity, the intersection between cellular or tissue mechanics and immune cell function, is emerging as an important factor in many inflammatory diseases. Mechano-sensing defines how cells detect mechanical changes in their environment. Mechano-response defines how cells adapt to such changes, e.g. form synapses, signal or migrate. Inflammasomes are intracellular immune sensors that detect changes in tissue and cell homoeostasis during infection or injury. We and others recently found that mechano-sensing of tissue topology (swollen tissue), topography (presence and distribution of foreign solid implant) or biomechanics (stiffness), alters inflammasome activity. Once activated, inflammasomes induce the secretion of inflammatory cytokines, but also change cellular mechanical properties, which influence how cells move, change their shape, and interact with other cells. When overactive, inflammasomes lead to chronic inflammation. This clearly places inflammasomes as important players in mechano-immunity. Here, we discuss a model whereby inflammasomes integrate pathogen- and tissue-injury signals, with changes in tissue mechanics, to shape the downstream inflammatory responses and allow cell and tissue mechano-adaptation. We will review the emerging evidence that supports this model.
    Keywords:  Foreign Body Reaction; Inflammasomes; Macrophages; Mechano-Responses; Mechano-Sensing
    DOI:  https://doi.org/10.1038/s44319-023-00008-2
  34. bioRxiv. 2023 Dec 13. pii: 2023.12.13.571550. [Epub ahead of print]
    Yeast EndoG prevents genome instability by degrading cytoplasmic DNA.
    Yang Yu, Xin Wang, Jordan Fox, Ruofan Yu, Pilendra Thakre, Brenna McCauley, Nicolas Nikoloutsos, Qian Li, P J Hastings, Weiwei Dang, Kaifu Chen, Grzegorz Ira.
      In metazoans release of mitochondrial DNA or retrotransposon cDNA to cytoplasm can cause sterile inflammation and disease. Cytoplasmic nucleases degrade these DNA species to limit inflammation. It remains unknown whether degradation these DNA also prevents nuclear genome instability. To address this question, we decided to identify the nuclease regulating transfer of these cytoplasmic DNA species to the nucleus. We used an amplicon sequencing-based method in yeast enabling analysis of millions of DSB repair products. Nu clear mt DNA (NUMTs) and retrotransposon cDNA insertions increase dramatically in nondividing stationary phase cells. Yeast EndoG (Nuc1) nuclease limits insertions of cDNA and transfer of very long mtDNA (>10 kb) that forms unstable circles or rarely insert in the genome, but it promotes formation of short NUMTs (∼45-200 bp). Nuc1 also regulates transfer of cytoplasmic DNA to nucleus in aging or during meiosis. We propose that Nuc1 preserves genome stability by degrading retrotransposon cDNA and long mtDNA, while short NUMTs can originate from incompletely degraded mtDNA. This work suggests that nucleases eliminating cytoplasmic DNA play a role in preserving genome stability.
    DOI:  https://doi.org/10.1101/2023.12.13.571550
  35. Front Neurosci. 2023 ;17 1321246
    Assessing causal associations between neurodegenerative diseases and neurological tumors with biological aging: a bidirectional Mendelian randomization study.
    Zhiyun Zhang, Ningfang Liu, Xuyang Pan, Chuyi Zhang, Yifan Yang, Xinyun Li, Ying Shao.
       Background: Aging is a significant risk factor for many neurodegenerative diseases and neurological tumors. Previous studies indicate that the frailty index, facial aging, telomere length (TL), and epigenetic aging clock acceleration are commonly used biological aging proxy indicators. This study aims to comprehensively explore potential relationships between biological aging and neurodegenerative diseases and neurological tumors by integrating various biological aging proxy indicators, employing Mendelian randomization (MR) analysis.
    Methods: Two-sample bidirectional MR analyses were conducted using genome-wide association study (GWAS) data. Summary statistics for various neurodegenerative diseases and neurological tumors, along with biological aging proxy indicators, were obtained from extensive meta-analyses of GWAS. Genetic single-nucleotide polymorphisms (SNPs) associated with the exposures were used as instrumental variables, assessing causal relationships between three neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis), two benign neurological tumors (vestibular schwannoma and meningioma), one malignant neurological tumor (glioma), and four biological aging indicators (frailty index, facial aging, TL, and epigenetic aging clock acceleration). Sensitivity analyses were also performed.
    Results: Our analysis revealed that genetically predicted longer TL reduces the risk of Alzheimer's disease but increases the risk of vestibular schwannoma and glioma (All Glioma, GBM, non-GBM). In addition, there is a suggestive causal relationship between some diseases (PD and GBM) and DNA methylation GrimAge acceleration. Causal relationships between biological aging proxy indicators and other neurodegenerative diseases and neurological tumors were not observed.
    Conclusion: Building upon prior investigations into the causal relationships between telomeres and neurodegenerative diseases and neurological tumors, our study validates these findings using larger GWAS data and demonstrates, for the first time, that Parkinson's disease and GBM may promote epigenetic age acceleration. Our research provides new insights and evidence into the causal relationships between biological aging and the risk of neurodegenerative diseases and neurological tumors.
    Keywords:  bidirectional Mendelian randomization study; biological aging; genome-wide association study (GWAS); neurodegenerative diseases; neurological tumors
    DOI:  https://doi.org/10.3389/fnins.2023.1321246
  36. medRxiv. 2023 Dec 14. pii: 2023.12.13.23299909. [Epub ahead of print]
    Machine learning models for blood pressure phenotypes combining multiple polygenic risk scores.
    Trans-Omics in Precision Medicine Consortium
      We construct non-linear machine learning (ML) prediction models for systolic and diastolic blood pressure (SBP, DBP) using demographic and clinical variables and polygenic risk scores (PRSs). We developed a two-model ensemble, consisting of a baseline model, where prediction is based on demographic and clinical variables only, and a genetic model, where we also include PRSs. We evaluate the use of a linear versus a non-linear model at both the baseline and the genetic model levels and assess the improvement in performance when incorporating multiple PRSs. We report the ensemble model's performance as percentage variance explained (PVE) on a held-out test dataset. A non-linear baseline model improved the PVEs from 28.1% to 30.1% (SBP) and 14.3% to 17.4% (DBP) compared with a linear baseline model. Including seven PRSs in the genetic model computed based on the largest available GWAS of SBP/DBP improved the genetic model PVE from 4.8% to 5.1% (SBP) and 4.7% to 5% (DBP) compared to using a single PRS. Adding additional 14 PRSs computed based on two independent GWASs further increased the genetic model PVE to 6.3% (SBP) and 5.7% (DBP). PVE differed across self-reported race/ethnicity groups, with primarily all non-White groups benefitting from the inclusion of additional PRSs.
    DOI:  https://doi.org/10.1101/2023.12.13.23299909
  37. J Physiol. 2024 Jan 03.
    Alterations in neuromuscular junction morphology with ageing and endurance training modulate neuromuscular transmission and myofibre composition.
    Tatsuhiro Yamaguchi, Karina Kouzaki, Kazushige Sasaki, Koichi Nakazato.
      Both ageing and exercise training affect the neuromuscular junction (NMJ) structure. Morphological alterations in the NMJ have been considered to influence neuromuscular transmission and myofibre properties, but the direct link between the morphology and function has yet to be established. We measured the neuromuscular transmission, myofibre composition and NMJ structure of 5-month-old (young) and 24-month-old untrained (aged control) and trained (aged trained) mice. Aged trained mice were subjected to 2 months of endurance training before the measurement. Neuromuscular transmission was evaluated in vivo as the ratio of ankle plantar flexion torque evoked by the sciatic nerve stimulation to that by direct muscle stimulation. The torque ratio was significantly lower in aged mice than in young and aged trained mice at high-frequency stimulations, showing a significant positive correlation with voluntary grip strength. The degree of pre- to post-synaptic overlap of the NMJ was also significantly lower in aged mice and positively correlated with the torque ratio. We also found that the proportion of fast-twitch fibres in the soleus muscle decreased with age, and that age-related denervation occurred preferentially in fast-twitch fibres. Age-related denervation and a shift in myofibre composition were partially prevented by endurance training. These results suggest that age-related deterioration of the NMJ structure impairs neuromuscular transmission and alters myofibre composition, but these alterations can be prevented by structural amelioration of NMJ with endurance training. Our findings highlight the importance of the NMJ as a major determinant of age-related deterioration of skeletal muscles and the clinical significance of endurance training as a countermeasure. KEY POINTS: The neuromuscular junction (NMJ) plays an essential role in neuromuscular transmission and the maintenance of myofibre properties. We show that neuromuscular transmission is impaired with ageing but recovered by endurance training, which contributes to alterations in voluntary strength. Neuromuscular transmission is associated with the degree of pre- to post-synaptic overlap of the NMJ. Age-related denervation of fast-twitch fibres and a shift in myofibre composition toward a slower phenotype are partially prevented by endurance training. Our study provides substantial evidence that age-related and exercise-induced alterations in neuromuscular transmission and myofibre properties are associated with morphological changes in the NMJ.
    Keywords:  age; denervation; exercise; motor unit; muscle strength; skeletal muscle
    DOI:  https://doi.org/10.1113/JP285143
  38. Int J Paleopathol. 2024 Jan 04. pii: S1879-9817(23)00076-1. [Epub ahead of print]44 90-104
    Perspectives on anemia: Factors confounding understanding of past occurrence.
    Megan B Brickley.
       OBJECTIVE: This paper reviews factors confounding the understanding of the past occurrence of anemia. Using the evidence gathered, a framework is presented of ways forward to enable greater confidence in diagnosing acquired anemia in paleopathology, facilitating insights into longer-term perspectives on this globally relevant condition.
    RESULTS: To date, porotic lesions have been central to paleopathological investigations of anemia. The fact that porotic bone lesions are omnipresent and have multiple causes but are likely to have a relatively low, age-related frequency in individuals with anemia, a condition that will have been common in past communities, is confounding.
    METHODS: Establishing frameworks that move away from porotic lesions is proposed to facilitate higher levels of more accurate anemia diagnoses in paleopathology.
    SIGNIFICANCE: Acceptance of the fundamental principle that anemia may be better considered as a condition requiring metric evaluation of bone structures, supplemented by careful consideration of lesions, will advance understanding of acquired anemia in past communities. Such an approach would provide a clear basis for further consideration of congenital conditions causing anemia, such as sickle-cell disease and thalassemia.
    LIMITATIONS: This paper simply opens the conversation on the better diagnosis of anemia in paleopathology; it starts the iterative process of achieving some consensus and progress on diagnosing anemia in paleopathology.
    SUGGESTIONS FOR FURTHER RESEARCH: Engagement with ideas presented, sharing data and development of metric parameters will assist in identifying the effects of marrow hyperplasia on bone, enabling more robust work on the important topic of anemia.
    Keywords:  Bioarchaeology; Cribra orbitalia; Porotic hyperostosis; Sickle-cell anemia; Thalassemia
    DOI:  https://doi.org/10.1016/j.ijpp.2023.12.001
  39. Brain Behav Immun. 2023 Dec 27. pii: S0889-1591(23)00412-9. [Epub ahead of print]
    Role of astrocyte senescence regulated by the non- canonical autophagy in the neuroinflammation associated to cerebral malaria.
    Fatima Hellani, Inès Leleu, Nasreddine Saidi, Nathalie Martin, Cécile Lecoeur, Elisabeth Werkmeister, David Koffi, François Trottein, Hélène Yapo-Etté, Bidyut Das, Corinne Abbadie, Sylviane Pied.
       BACKGROUND: Cerebral malaria (CM) is a fatal neuroinflammatory syndrome caused (in humans) by the protozoa Plasmodium (P.) falciparum. Glial cell activation is one of the mechanisms that contributes to neuroinflammation in CM.
    RESULT: By studying a mouse model of CM (caused by P. berghei ANKA), we describe that the induction of autophagy promoted p21-dependent senescence in astrocytes and that CXCL-10 was part of the senescence-associated secretory phenotype. Furthermore, p21 expression was observed in post-mortem brain and peripheral blood samples from patients with CM. Lastly, we found that the depletion of senescent astrocytes with senolytic drugs abrogated inflammation and protected mice from CM.
    CONCLUSION: our data provide evidence for a novel mechanism through which astrocytes could be involved in the neuropathophysiology of CM. p21 gene expression in blood cell and an elevated plasma CXCL-10 concentration could be valuable biomarkers of CM in humans. In the end, we believe senolytic drugs shall open up new avenues to develop newer treatment options.
    Keywords:  Astrocyte; Cellular senescence; Cerebral malaria; Inflammation; P21; Senolytic drugs
    DOI:  https://doi.org/10.1016/j.bbi.2023.12.030
  40. Geroscience. 2024 Jan 04.
    Cell Tree Rings: the structure of somatic evolution as a human aging timer.
    Attila Csordas, Botond Sipos, Terezia Kurucova, Andrea Volfova, Frantisek Zamola, Boris Tichy, Damien G Hicks.
      Biological age is typically estimated using biomarkers whose states have been observed to correlate with chronological age. A persistent limitation of such aging clocks is that it is difficult to establish how the biomarker states are related to the mechanisms of aging. Somatic mutations could potentially form the basis for a more fundamental aging clock since the mutations are both markers and drivers of aging and have a natural timescale. Cell lineage trees inferred from these mutations reflect the somatic evolutionary process, and thus, it has been conjectured, the aging status of the body. Such a timer has been impractical thus far, however, because detection of somatic variants in single cells presents a significant technological challenge. Here, we show that somatic mutations detected using single-cell RNA sequencing (scRNA-seq) from thousands of cells can be used to construct a cell lineage tree whose structure correlates with chronological age. De novo single-nucleotide variants (SNVs) are detected in human peripheral blood mononuclear cells using a modified protocol. A default model based on penalized multiple regression of chronological age on 31 metrics characterizing the phylogenetic tree gives a Pearson correlation of 0.81 and a median absolute error of ~4 years between predicted and chronological ages. Testing of the model on a public scRNA-seq dataset yields a Pearson correlation of 0.85. In addition, cell tree age predictions are found to be better predictors of certain clinical biomarkers than chronological age alone, for instance glucose, albumin levels, and leukocyte count. The geometry of the cell lineage tree records the structure of somatic evolution in the individual and represents a new modality of aging timer. In addition to providing a numerical estimate of "cell tree age," it unveils a temporal history of the aging process, revealing how clonal structure evolves over life span. Cell Tree Rings complements existing aging clocks and may help reduce the current uncertainty in the assessment of geroprotective trials.
    Keywords:  Biological age; Cell Tree Rings; Geroprotective trials
    DOI:  https://doi.org/10.1007/s11357-023-01053-4
  41. Phytomedicine. 2023 Dec 14. pii: S0944-7113(23)00640-2. [Epub ahead of print]124 155282
    Mangiferin attenuates osteoporosis by inhibiting osteoblastic ferroptosis through Keap1/Nrf2/SLC7A11/GPX4 pathway.
    Xuehui Deng, Bingfeng Lin, Fang Wang, Pingcui Xu, Nani Wang.
       BACKGROUND: Ferroptosis is a crucial contributor to impaired osteoblast function in osteoporosis. Mangiferin, a xanthonoid glucoside isolated from mangoes, exhibits anti-osteoporosis effects. However, its potential mechanism is not fully understood.
    PURPOSE: This study explores the potencies of mangiferin on osteoblastic ferroptosis and deciphers its direct target in the context of solute carrier family 7-member 11 (SLC7A11)/glutathione peroxidases 4 (GPX4) pathway.
    METHODS: In vivo models include bilateral ovariectomy induced osteoporosis mice, iron-dextran induced iron-overloaded mice, and nuclear factor-erythroid 2-related factor 2 (Nrf2)-knockout mice. Mice are orally administrated mangiferin (10, 50 or 100 mg.kg-1.d-1) for 12 weeks. In vitro osteoblast models include iron-dextran induced iron-overloaded cells, erastin induced ferroptosis cells, and gene knockout cells. RNA sequencing is applied for investigating the underlying mechanisms. The direct target of mangiferin is studied using a cellular thermal shift assay, silico docking, and surface plasmon resonance.
    RESULTS: Mangiferin promotes bone formation and inhibits ferroptosis in vivo models (osteoporosis mice, iron-overloaded mice) and in vitro models (ferroptosis osteoblast, iron-overloaded osteoblasts). Mechanismly, mangiferin directly binds to the kelch-like ECH-associated protein 1 (Keap1) and activates the downstream Nrf2/SLC7A11/GPX4 pathway in both the in vivo and in vitro models. Mangiferin failed to restore the osteoporosis and ferroptosis in Nrf2-knockout mice. Silencing Nrf2, SLC7A11 or GPX4 abolished the anti-ferroptosis effect of mangiferin in erastin-induced cells. Addition of the ferroptosis agonist RSL-3 also blocked the protective effects of mangiferin on iron-overloaded cells. Furthermore, mangiferin had better effects on osteogenesis than the ferroptosis inhibitor (ferrostatin-1) and the Nrf2 agonists (sulforaphane, dimethyl fumarate, and bardoxolone).
    CONCLUSIONS: We identify for the first time mangiferin as a ferroptosis inhibitor and a direct Keap1 conjugator that promotes bone formation and alleviates osteoporosis. This work also provides a potentially practical pharmacological approach for treating ferroptosis-driven diseases.
    Keywords:  Ferroptosis; GPX4; Mangiferin; Osteoblast; Osteoporosis; SLC7A11
    DOI:  https://doi.org/10.1016/j.phymed.2023.155282
  42. Biol Open. 2023 Dec 29. pii: bio.060261. [Epub ahead of print]
    Aging disrupts spatiotemporal regulation of germline stem cells and niche integrity.
    Michelle A Urman, Nimmy S John, Tyler Jung, ChangHwan Lee.
      A major factor driving stem cell decline is stem cell niche aging, but its molecular mechanism remains elusive. We use the Caenorhabditis elegans distal tip cell (DTC), the mesenchymal niche that employs Notch signaling to regulate germline stem cells (GSCs), as an in vivo niche aging model and delineate the molecular details of the DTC/niche aging process. Here, we demonstrate that a drastic decrease in C. elegans germline fecundity, which begins even in early adulthood, is mainly due to an age-induced disruption in spatial regulation of Notch-dependent transcription in the germline combined with a moderate reduction in Notch transcription at both tissue and cellular levels. Consequently, the Notch-responsive GSC pool shifts from the distal end of the gonad to a more proximal region, disrupting the distal-to-proximal germline polarity. We find that this GSC pool shift is due to a dislocation of the DTC/niche nucleus, which is associated with age-induced changes in the structure and morphology of the DTC/niche. Our findings reveal a critical link between physiological changes in the aging niche, their consequences in stem cell regulation, and germline tissue functions.
    Keywords:   Caenorhabditis elegans gonad; sygl-1 ; Aging; Germline stem cells; Gradient; Notch signaling; Spatial pattern analysis; Transcriptional regulation
    DOI:  https://doi.org/10.1242/bio.060261
  43. Free Radic Biol Med. 2023 Dec 28. pii: S0891-5849(23)01192-9. [Epub ahead of print]
    Lactoferrin ameliorated obesity-induced endothelial dysfunction by inhibiting the Tak1/IL-18/eNOS pathway between PVAT and vascular endothelium.
    Cailong Chen, Yilin Yan, Yunxuan Wu, Menglan Lu, Yifei Xing, Yujie Bai, Haodong Zhao, Li Ding, Ying Wu, Jiaying Xu, Liqiang Qin, Haitao Lv, Zheng Zhang.
      Vascular endothelial dysfunction (ED) is one of the mechanisms underlying obesity-related hypertension. Perivascular adipose tissue (PVAT) surrounds blood vessels and influences the vascular endothelium function. Previous studies have demonstrated the antihypertensive effects of lactoferrin (LF) and its hydrolysates through various mechanisms. However, the effect of LF on ED and PVAT has not yet been investigated. In this study, we examined the influence of LF on ED and PVAT using high-fat diet mice as well as MAEC cells and 3T3-L1 adipocytes. Finally, LF supplementation decreases the systolic blood pressure (SBP), serum adhesion molecule (ICAM-1 and VCAM-1), and aorta ROS levels, and improves endothelium-dependent relaxation function in high-fat diet mice. Moreover, LF supplementation down-regulates the Tak1/IL-18/eNOS pathway between PVAT and aorta and enhances the NO generation in high-fat diet mice. In addition, we observe that LF decreases the expression levels of IL-18 and p-Tak1 in 3T3-L1 adipocytes, but fails to influence the eNOS and p-eNOS expression levels in MAEC cells. Finally, the significant associations between LF and IL-18 and SBP and hypertension risk are also observed in obesity children only. These findings provide evidence that the Tak1/IL-18/eNOS pathway between the aorta and PVAT is important in obesity-related ED, and LF may improve ED or even hypertension by down-regulating this pathway.
    Keywords:  Endothelial dysfunction; High-fat diet; IL-18; Lactoferrin; Nitric oxide
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.12.036
  44. Front Cell Neurosci. 2023 ;17 1290628
    Using focused ultrasound to modulate microglial structure and function.
    Sarina Grewal, Elisa Gonçalves de Andrade, Rikke Hahn Kofoed, Paul M Matthews, Isabelle Aubert, Marie-Ève Tremblay, Sophie V Morse.
      Transcranial focused ultrasound (FUS) has the unique ability to target regions of the brain with high spatial precision, in a minimally invasive manner. Neuromodulation studies have shown that FUS can excite or inhibit neuronal activity, demonstrating its tremendous potential to improve the outcome of neurological diseases. Recent evidence has also shed light on the emerging promise that FUS has, with and without the use of intravenously injected microbubbles, in modulating the blood-brain barrier and the immune cells of the brain. As the resident immune cells of the central nervous system, microglia are at the forefront of the brain's maintenance and immune defense. Notably, microglia are highly dynamic and continuously survey the brain parenchyma by extending and retracting their processes. This surveillance activity aids microglia in performing key physiological functions required for brain activity and plasticity. In response to stressors, microglia rapidly alter their cellular and molecular profile to help facilitate a return to homeostasis. While the underlying mechanisms by which both FUS and FUS + microbubbles modify microglial structure and function remain largely unknown, several studies in adult mice have reported changes in the expression of the microglia/macrophage marker ionized calcium binding adaptor molecule 1, and in their phagocytosis, notably of protein aggregates, such as amyloid beta. In this review, we discuss the demonstrated and putative biological effects of FUS and FUS + microbubbles in modulating microglial activities, with an emphasis on the key cellular and molecular changes observed in vitro and in vivo across models of brain health and disease. Understanding how this innovative technology can modulate microglia paves the way for future therapeutic strategies aimed to promote beneficial physiological microglial roles, and prevent or treat maladaptive responses.
    Keywords:  blood-brain barrier; focused ultrasound; functional effects; glia; microglia; modulation; neurodegeneration
    DOI:  https://doi.org/10.3389/fncel.2023.1290628
  45. Biophys J. 2024 Jan 04. pii: S0006-3495(24)00001-8. [Epub ahead of print]
    Phosphomimetic substitutions in TDP-43's transiently α-helical region suppress phase separation.
    Raza Haider, Srinivasa Penumutchu, Solomiia Boyko, Witold K Surewicz.
      Phosphorylated TAR DNA-binding protein of 43 kDa (TDP-43) is present within the aggregates of several age-related neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) and Alzheimer's disease, to the point that the presence of phosphorylated TDP-43 is considered a hallmark of some of these diseases. The majority of known TDP-43 phosphorylation sites detected in ALS/FTLD patients is located in the low complexity domain (LCD), the same domain that has been shown to be critical for TDP-43 liquid-liquid phase separation (LLPS). However, the effect of these LCD phosphorylation sites on TDP-43 LLPS has been largely unexplored, and any work that has been done has largely focused on sites near the C-terminal end of the LCD. Here, we used a phosphomimetic approach to explore the impact of phosphorylation at residues S332 and S333, sites located within the transiently α-helical region of TDP-43 that have been observed to be phosphorylated in disease, on protein LLPS. Our turbidimetry and fluorescence microscopy data demonstrate that these phosphomimetic substitutions greatly suppress LLPS, and solution NMR data strongly suggest that this effect is at least in part due to the loss of α-helical propensity of the phosphomimetic protein variant. We also show that the S332D and S333D substitutions slow TDP-43 LCD droplet aging and fibrillation of the protein. Overall, these findings provide a biophysical basis for understanding the effect of phosphorylation within the transiently α-helical region of TDP-43 LCD on protein LLPS and fibrillation, suggesting that phosphorylation at residues 332 and 333 is not necessarily directly related to the pathogenic process.
    Keywords:  TAR DNA-binding protein of 43 kDa (TDP-43); amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease); intrinsically-disordered protein; liquid-liquid phase separation; neurodegenerative diseases; protein aggregation; protein phosphorylation
    DOI:  https://doi.org/10.1016/j.bpj.2024.01.001
  46. Cell Death Dis. 2024 Jan 04. 15(1): 4
    Screens in aging-relevant human ALS-motor neurons identify MAP4Ks as therapeutic targets for the disease.
    Meng-Lu Liu, Shuaipeng Ma, Wenjiao Tai, Xiaoling Zhong, Haoqi Ni, Yuhua Zou, Jingcheng Wang, Chun-Li Zhang.
      Effective therapeutics is much needed for amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease mainly affecting motor neurons. By screening chemical compounds in human patient-derived and aging-relevant motor neurons, we identify a neuroprotective compound and show that MAP4Ks may serve as therapeutic targets for treating ALS. The lead compound broadly improves survival and function of motor neurons directly converted from human ALS patients. Mechanistically, it works as an inhibitor of MAP4Ks, regulates the MAP4Ks-HDAC6-TUBA4A-RANGAP1 pathway, and normalizes subcellular distribution of RANGAP1 and TDP-43. Finally, in an ALS mouse model we show that inhibiting MAP4Ks preserves motor neurons and significantly extends animal lifespan.
    DOI:  https://doi.org/10.1038/s41419-023-06395-7
  47. Acta Biomater. 2023 Dec 28. pii: S1742-7061(23)00750-X. [Epub ahead of print]
    Paracrine cross-talk between human adipose tissue-derived endothelial cells and perivascular cells accelerates the endothelialization of an electrospun ionomeric polyurethane scaffold.
    Jeremy A Antonyshyn, Kate D MacQuarrie, Meghan J McFadden, Anthony O Gramolini, Stefan O P Hofer, J Paul Santerre.
      The ex vivo endothelialization of small diameter vascular prostheses can prolong their patency. Here, we demonstrate that heterotypic interactions between human adipose tissue-derived endothelial cells and perivascular cells can be exploited to accelerate the endothelialization of an electrospun ionomeric polyurethane scaffold. The scaffold was used to physically separate endothelial cells from perivascular cells to prevent their diffuse neo-intimal hyperplasia and spontaneous tubulogenesis, yet enable their paracrine cross-talk to accelerate the integration of the endothelial cells into a temporally stable endothelial lining of a continuous, elongated, and aligned morphology. Perivascular cells stimulated endothelial basement membrane protein production and suppressed their angiogenic and inflammatory activation to accelerate this biomimetic morphogenesis of the endothelium. These findings demonstrate the feasibility and underscore the value of exploiting heterotypic interactions between endothelial cells and perivascular cells for the fabrication of an endothelial lining intended for small diameter arterial reconstruction. STATEMENT OF SIGNIFICANCE: Adipose tissue is an abundant, accessible, and uniquely dispensable source of endothelial cells and perivascular cells for vascular tissue engineering. While their spontaneous self-assembly into microvascular networks is routinely exploited for the vascularization of engineered tissues, it threatens the temporal stability of an endothelial lining intended for small diameter arterial reconstruction. Here, we demonstrate that an electrospun polyurethane scaffold can be used to physically separate endothelial cells from perivascular cells to prevent their spontaneous capillary morphogenesis, yet enable their cross-talk to promote the formation of a stable endothelium. Our findings demonstrate the feasibility of engineering an endothelial lining from human adipose tissue, poising it for the rapid ex vivo endothelialization of small diameter vascular prostheses in an autologous, patient-specific manner.
    Keywords:  Adipose tissue; Basement membrane; Electrospinning; Endothelial cells; Perivascular cells; Polyurethane
    DOI:  https://doi.org/10.1016/j.actbio.2023.12.037
  48. J Mol Biol. 2023 Dec 28. pii: S0022-2836(23)00541-7. [Epub ahead of print] 168424
    Mechanisms of Immune Sensing of DNA Damage.
    Anna M Goddard, Min-Guk Cho, Lynn M Lerner, Gaorav P Gupta.
      Genomic stability relies on a multifaceted and evolutionarily conserved DNA damage response (DDR). In multicellular organisms, an integral facet of the DDR involves the activation of the immune system to eliminate cells with persistent DNA damage. Recent research has shed light on a complex array of nucleic acid sensors crucial for innate immune activation in response to oncogenic stress-associated DNA damage, a process vital for suppressing tumor formation. Yet, these immune sensing pathways may also be co-opted to foster tolerance of chromosomal instability, thereby driving cancer progression. This review aims to provide an updated overview of how the innate immune system detects and responds to DNA damage. An improved understanding of the regulatory intricacies governing this immune response may uncover new avenues for cancer prevention and therapeutic intervention.
    Keywords:  DNA Damage; Immune sensing; RNA sensing; Sensors of replication-associated DNA damage; cGAS-STING; cytosolic DNA sensing
    DOI:  https://doi.org/10.1016/j.jmb.2023.168424
  49. Neurotherapeutics. 2022 Jan;pii: S1878-7479(23)00178-2. [Epub ahead of print]19(1): 421-433
    Chronic Administration of 13-cis-retinoic Acid Induces Depression-Like Behavior by Altering the Activity of Dentate Granule Cells.
    Xiao-Hong Su, Wei-Peng Li, Yi-Jie Wang, Jia Liu, Jun-Yu Liu, Ying Jiang, Fu-Hua Peng.
      Depression is a common but serious mental disorder and can be caused by the side effects of medications. Evidence from abundant clinical case reports and experimental animal models has revealed the association between the classic anti-acne drug 13-cis-retinoic acid (13-cis-RA) and depressive symptoms. However, direct experimental evidence of this mechanism and information on appropriate therapeutic rescue strategies are lacking. Herein, our data revealed that chronic administration of 13-cis-RA to adolescent mice induced depression-like behavior but not anxiety-like behavior. We next demonstrated that chronic 13-cis-RA application increased neural activity in the dentate gyrus (DG) using c-Fos immunostaining, which may be critically involved in some aspects of depression-like behavior. Therefore, we assessed electrophysiological functions by obtaining whole-cell patch-clamp recordings of dentate granule cells (DGCs), which revealed that chronic 13-cis-RA treatment shifted the excitatory-inhibitory balance toward excitation and increased intrinsic excitability. Furthermore, a pharmacogenetic approach was performed to repeatedly silence DGCs, and this manipulation could rescue depression-like behavior in chronically 13-cis-RA-treated mice, suggesting DGCs as a potential cellular target for the direct alleviation of 13-cis-RA-induced depression.
    Keywords:  13-cis-retinoic acid; Dentate gyrus; Depression; Excitation/inhibition balance; Intrinsic membrane properties
    DOI:  https://doi.org/10.1007/s13311-021-01168-6
  50. Curr Rheumatol Rep. 2023 Dec 29.
    Synovial Tissue Insights into Heterogeneity of Rheumatoid Arthritis.
    Anna Helena Jonsson.
       PURPOSE OF REVIEW: Rheumatoid arthritis is one of the most common rheumatic and autoimmune diseases. While it can affect many different organ systems, RA primarily involves inflammation in the synovium, the tissue that lines joints. Patients with RA exhibit significant clinical heterogeneity in terms of presence or absence of autoantibodies, degree of permanent deformities, and most importantly, treatment response. These clinical characteristics point to heterogeneity in the cellular and molecular pathogenesis of RA, an area that several recent studies have begun to address.
    RECENT FINDINGS: Single-cell RNA-sequencing initiatives and deeper focused studies have revealed several RA-associated cell populations in synovial tissues, including peripheral helper T cells, autoimmunity-associated B cells (ABCs), and NOTCH3+ sublining fibroblasts. Recent large transcriptional studies and translational clinical trials present frameworks to capture cellular and molecular heterogeneity in RA synovium. Technological developments, such as spatial transcriptomics and machine learning, promise to further elucidate the different types of RA synovitis and the biological mechanisms that characterize them, key elements of precision medicine to optimize patient care and outcomes in RA. This review recaps the findings of those recent studies and puts our current knowledge and future challenges into scientific and clinical perspective.
    Keywords:  Autoimmune disease; Disease heterogeneity; Rheumatoid arthritis; Synovial tissue; Tissue inflammation
    DOI:  https://doi.org/10.1007/s11926-023-01129-2
  51. Trends Cell Biol. 2023 Dec 29. pii: S0962-8924(23)00253-2. [Epub ahead of print]
    An ATM D-compartmentalization in DNA damage response.
    Anjali Prasad, Arun Kanakkanthara.
      How chromatin configuration impacts DNA repair is an emerging question. A recent study by Arnould et al. shows that ATM orchestrates a new chromatin compartment (D compartment) following DNA double-strand breaks and establishes that this compartment enhances cellular response to such breaks but also introduces a risk to genome integrity.
    Keywords:  ATM; D compartment; DNA damage response; DNA repair; chromatin compartmentalization; genome integrity
    DOI:  https://doi.org/10.1016/j.tcb.2023.12.003
  52. J Physiol Biochem. 2023 Dec 30.
    N6-methyladenosine in myeloid cells: a novel regulatory factor for inflammation-related diseases.
    Jin Pang, Tong-Dong Kuang, Xin-Yuan Yu, Petr Novák, Yuan Long, Min Liu, Wei-Qian Deng, Xiao Zhu, Kai Yin.
      N6-methyladenosine (m6A) is one of the most abundant epitranscriptomic modifications on eukaryotic mRNA. Evidence has highlighted that m6A is altered in response to inflammation-related factors and it is closely associated with various inflammation-related diseases. Multiple subpopulations of myeloid cells, such as macrophages, dendritic cells, and granulocytes, are crucial for the regulating of immune process in inflammation-related diseases. Recent studies have revealed that m6A plays an important regulatory role in the functional of multiple myeloid cells. In this review, we comprehensively summarize the function of m6A modification in myeloid cells from the perspective of myeloid cell production, activation, polarization, and migration. Furthermore, we discuss how m6A-mediated myeloid cell function affects the progression of inflammation-related diseases, including autoimmune diseases, chronic metabolic diseases, and malignant tumors. Finally, we discuss the challenges encountered in the study of m6A in myeloid cells, intended to provide a new direction for the study of the pathogenesis of inflammation-related diseases.
    Keywords:  Inflammation-related diseases; Myeloid cells; N6-methyladenosine
    DOI:  https://doi.org/10.1007/s13105-023-01002-x
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