bims-caglex Biomed News
on Cellular aging and life extension
Issue of 2024–09–08
68 papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño
  1. Senolytics target cellular senescence - but can they slow aging?
  2. Advances in Nanotherapy for Targeting Senescent Cells.
  3. Analysis of the senescence-associated cell surfaceome reveals potential senotherapeutic targets.
  4. Fasting and calorie restriction modulate age-associated immunosenescence and inflammaging.
  5. Particulate matter 2.5 accelerates aging: Exploring cellular senescence and age-related diseases.
  6. Topical ABT-263 treatment reduces aged skin senescence and improves subsequent wound healing.
  7. The Potential of Mitochondrial Therapeutics in the Treatment of Oxidative Stress and Inflammation in Aging.
  8. Role of the central nervous system in cell non-autonomous signaling mechanisms of aging and longevity in mammals.
  9. Ribosomal S6 kinase 1 regulates inflammaging via the senescence secretome.
  10. Polygenic proxies of age-related plasma protein levels reveal TIMP2 role in cognitive performance.
  11. Lycium barbarum berry extract improves female fertility against aging-related oxidative stress in the ovary.
  12. Nerol mitigates dexamethasone-induced skin aging by activating the Nrf2 signaling pathway in human dermal fibroblasts.
  13. Mitochondria-Associated Membranes in Aging and Senescence.
  14. Effect of aging and exercise on hTERT expression in thymus tissue of hTERT transgenic bacterial artificial chromosome mice.
  15. Defying "IL-11ness" by inhibiting inflammation: Strategy for health and longevity.
  16. Bone Tissue Engineering with Adipose-Derived Stem Cells in Polycaprolactone/Graphene Oxide/Dexamethasone 3D-Printed Scaffolds.
  17. Glycosylation in aging and neurodegenerative diseases.
  18. Allostatic load in rat model: An efficient tool for evaluating and understanding aging.
  19. Sequential Targeted Enzyme-Instructed Self-Assembly Supramolecular Nanofibers to Attenuate Intervertebral Disc Degeneration.
  20. Barleriside A, an aryl hydrocarbon receptor antagonist, ameliorates podocyte injury through inhibiting oxidative stress and inflammation.
  21. Potential implications of natural compounds on aging and metabolic regulation.
  22. Use of qPCR to Evaluate Efficiency of the Bulky DNA Damage Removal in Extracts of Mammalian Cells with Different Maximum Lifespan.
  23. Loss of coordination between basic cellular processes in human aging.
  24. Periodic protein-restricted diets extend the lifespan of high-fat diet-induced Drosophila melanogaster males.
  25. HPPE Activates NRF2 Signaling by Liberating Heavy Metal Stores.
  26. Cellular Senescence in Diffuse Gliomas: From Physiopathology to Possible Treatments.
  27. An in-depth understanding of the role and mechanisms of T cells in immune organ aging and age-related diseases.
  28. Multifaceted role of the DNA replication protein MCM10 in maintaining genome stability and its implication in human diseases.
  29. Telomere stabilization by metformin mitigates the progression of atherosclerosis via the AMPK-dependent p-PGC-1α pathway.
  30. Blockade of dopamine D3 receptors improves hippocampal synaptic function and rescues age-related cognitive phenotype.
  31. Finding the Balance to Quiet the Striving: The Difference Between Successful Aging and Wise Aging.
  32. Rejuvenation of the reconstitution potential and reversal of myeloid bias of aged HSCs upon pH treatment.
  33. Stress Hormones: Unveiling the Role in Accelerated Cellular Senescence.
  34. A surge in endogenous spermidine is essential for rapamycin-induced autophagy and longevity.
  35. Differences in the Effect of Beta-Hydroxybutyrate on the Mitochondrial Biogenesis, Oxidative Stress and Inflammation Markers in Tissues from Young and Old Rats.
  36. IL-33 prevents age-related bone loss and memory impairment by suppression of Th17 response: evidence in a d-galactose-induced aging mouse model.
  37. DNA methylation by CcrM contributes to genome maintenance in the Agrobacterium tumefaciens plant pathogen.
  38. Inhibition of the RXRA-PPARα-FABP4 signaling pathway alleviates vascular cellular aging by an SGLT2 inhibitor in an atherosclerotic mice model.
  39. Gene-Specific Machine Learning Models to Classify Driver Mutations in Clonal Hematopoiesis.
  40. Nitrate: "the source makes the poison".
  41. Hyaluronan and proteoglycan link protein 1 - a novel signaling molecule for rejuvenating aged skin.
  42. Effects of Caloric Restriction and Intermittent Fasting and Their Combined Exercise on Cognitive Functioning: A Review.
  43. ImAge quantitates aging and rejuvenation.
  44. Stromal cells and epigenetics: emerging key players of chronic inflammatory skin diseases.
  45. Mitochondrial Adaptations in Aging Skeletal Muscle: Implications for Resistance Exercise Training to Treat Sarcopenia.
  46. PENG ZU Study on Healthy Aging in China (PENG ZU Cohort): Design and Goals.
  47. Yeast EndoG prevents genome instability by degrading extranuclear DNA species.
  48. Structural characterization, anti-aging activity and mechanisms investigation in vivo of a polysaccharide from Anthriscus sylvestris.
  49. Regulatory Mechanisms of Natural Active Ingredients and Compounds on Keratinocytes and Fibroblasts in Mitigating Skin Photoaging.
  50. Recognition and Sequencing of Mutagenic DNA Adduct at Single-Base Resolution Through Unnatural Base Pair.
  51. Engineered exosome therapeutics for neurodegenerative diseases.
  52. The CALERIE™ Genomic Data Resource.
  53. ABHD8 antagonizes inflammation by facilitating chaperone-mediated autophagy-mediated degradation of NLRP3.
  54. Mesenchymal stem cells derived from human adipose tissue exhibit significantly higher chondrogenic differentiation potential compared to those from rats.
  55. Researchers built an 'AI Scientist' - what can it do?
  56. DNA stimulates SIRT6 to mono-ADP-ribosylate proteins within histidine repeats.
  57. A Single-Cell Metabolic Profiling Characterizes Human Aging via SlipChip-SERS.
  58. Causal linkage of psoriasis with ageing: Mendelian randomization and enrichment analysis towards telomere length and psoriasis.
  59. DNA Methyltransferase Inhibition by RG108 Improves Stemness and Multipotential Differentiation of Human Adipose Tissue-derived Stem Cells.
  60. A new clinical age of aging research.
  61. Macrofungal Extracts as a Source of Bioactive Compounds for Cosmetical Anti-Aging Therapy: A Comprehensive Review.
  62. Zuogui Pills Improve the Learning and Memory Ability of Brain-Aging Mice through the Estrogen Receptor ERα Methylation Pathway.
  63. Ophthalmic acid is a bloodborne metabolite that contributes to age-induced cardiomyocyte hypertrophy.
  64. Activation and inhibition of sirtuins: From bench to bedside.
  65. A bioswitchable delivery system for microRNA therapeutics based on a tetrahedral DNA nanostructure.
  66. Calcium silicate cements endowing bioactivity and sustaining mechanical strength of low-heat-releasing and fast-curing magnesium phosphate cements.
  67. Macrophage WDFY3, a protector against autoimmunity.
  68. Cell-Permeable Nicotinamide Adenine Dinucleotides for Exploration of Cellular Protein ADP-Ribosylation.
  1. Nat Med. 2024 Sep 02.
    Senolytics target cellular senescence - but can they slow aging?
    Natalie Healey.
      
    DOI:  https://doi.org/10.1038/d41591-024-00067-5
  2. Int J Nanomedicine. 2024 ;19 8797-8813
    Advances in Nanotherapy for Targeting Senescent Cells.
    Yurou Shi, Yingjie Zhang, Yaxuan Zhang, Jiali Yao, Junping Guo, Xiaoling Xu, Lijun Wang.
      Aging is an inevitable process in the human body, and cellular senescence refers to irreversible cell cycle arrest caused by external aging-promoting mechanisms. Moreover, as age increases, the accumulation of senescent cells limits both the health of the body and lifespan and even accelerates the occurrence and progression of age-related diseases. Therefore, it is crucial to delay the periodic irreversible arrest and continuous accumulation of senescent cells to address the issue of aging. The fundamental solution is targeted therapy focused on eliminating senescent cells or reducing the senescence-associated secretory phenotype. Over the past few decades, the remarkable development of nanomaterials has revolutionized clinical drug delivery pathways. Their unique optical, magnetic, and electrical properties effectively compensate for the shortcomings of traditional drugs, such as low stability and short half-life, thereby maximizing the bioavailability and minimizing the toxicity of drug delivery. This article provides an overview of how nanomedicine systems control drug release and achieve effective diagnosis. By presenting and analyzing recent advances in nanotherapy for targeting senescent cells, the underlying mechanisms of nanomedicine for senolytic and senomorphic therapy are clarified, providing great potential for targeting senescent cells.
    Keywords:  calcium carbonate nanoparticles; liposomes; mesoporous silica nanoparticles; nanoemulsions; senescent cells
    DOI:  https://doi.org/10.2147/IJN.S469110
  3. Aging Cell. 2024 Sep 03. e14312
    Analysis of the senescence-associated cell surfaceome reveals potential senotherapeutic targets.
    Yushuang Deng, Ting Liu, Enzo Scifo, Tao Li, Kan Xie, Bernd Taschler, Sarah Morsy, Kristina Schaaf, Armin Ehninger, Daniele Bano, Dan Ehninger.
      The accumulation of senescent cells is thought to play a crucial role in aging-associated physiological decline and the pathogenesis of various age-related pathologies. Targeting senescence-associated cell surface molecules through immunotherapy emerges as a promising avenue for the selective removal of these cells. Despite its potential, a thorough characterization of senescence-specific surface proteins remains to be achieved. Our study addresses this gap by conducting an extensive analysis of the cell surface proteome, or "surfaceome", in senescent cells, spanning various senescence induction regimes and encompassing both murine and human cell types. Utilizing quantitative mass spectrometry, we investigated enriched cell surface proteins across eight distinct models of senescence. Our results uncover significant changes in surfaceome expression profiles during senescence, highlighting extensive modifications in cell mechanics and extracellular matrix remodeling. Our research also reveals substantive heterogeneity of senescence, predominantly influenced by cell type and senescence inducer. A key discovery of our study is the identification of four unique cell surface proteins with extracellular epitopes. These proteins are expressed in senescent cells, absent or present at low levels in their proliferating counterparts, and notably upregulated in tissues from aged mice and an Alzheimer's disease mouse model. These proteins stand out as promising candidates for senotherapeutic targeting, offering potential pathways for the detection and strategic targeting of senescent cell populations in aging and age-related diseases.
    Keywords:  aging; cell surface proteins; cellular senescence; mass spectrometry; senotherapeutics
    DOI:  https://doi.org/10.1111/acel.14312
  4. Aging Med (Milton). 2024 Aug;7(4): 499-509
    Fasting and calorie restriction modulate age-associated immunosenescence and inflammaging.
    Anteneh Mehari Tizazu.
      Aging is a multifaceted process impacting cells, tissues, organs, and organ systems of the body. Like other systems, aging affects both the adaptive and the innate components of the immune system, a phenomenon known as immunosenescence. The deregulation of the immune system puts elderly individuals at higher risk of infection, lower response to vaccines, and increased incidence of cancer. In the Western world, overnutrition has increased the incidence of obesity (linked with chronic inflammation) which increases the risk of metabolic syndrome, cardiovascular disease, and cancer. Aging is also associated with inflammaging a sterile chronic inflammation that predisposes individuals to age-associated disease. Genetic manipulation of the nutrient-sensing pathway, fasting, and calorie restriction (CR) has been shown to increase the lifespan of model organisms. As well in humans, fasting and CR have also been shown to improve different health parameters. Yet the direct effect of fasting and CR on the aging immune system needs to be further explored. Identifying the effect of fasting and CR on the immune system and how it modulates different parameters of immunosenescence could be important in designing pharmacological or nutritional interventions that slow or revert immunosenescence and strengthen the immune system of elderly individuals. Furthermore, clinical intervention can also be planned, by incorporating fasting or CR with medication, chemotherapy, and vaccination regimes. This review discusses age-associated changes in the immune system and how these changes are modified by fasting and CR which add information on interventions that promote healthy aging and longevity in the growing aging population.
    Keywords:  aging; calorie restriction; fasting; immunosenescence; inflammaging
    DOI:  https://doi.org/10.1002/agm2.12342
  5. Ecotoxicol Environ Saf. 2024 Aug 28. pii: S0147-6513(24)00996-5. [Epub ahead of print]284 116920
    Particulate matter 2.5 accelerates aging: Exploring cellular senescence and age-related diseases.
    Sheng-Nan Wang, Yan-Chuan Shi, Shu Lin, He-Fan He.
      Exposure to Particulate matter 2.5 (PM2.5) accelerates aging, causing declines in tissue and organ function, and leading to diseases such as cardiovascular, neurodegenerative, and musculoskeletal disorders. PM2.5 is a major environmental pollutant and an exogenous pathogen in air pollution that is now recognized as an accelerator of human aging and a predisposing factor for several age-related diseases. In this paper, we seek to elucidate the mechanisms by which PM2.5 induces cellular senescence, such as genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, and mitochondrial dysfunction, and age-related diseases. Our goal is to increase awareness among researchers within the field of the toxicity of environmental pollutants and to advocate for personal and public health initiatives to curb their production and enhance population protection. Through these endeavors, we aim to promote longevity and health in older adults.
    Keywords:  Age-related diseases; Aging; Cellular senescence; Particulate matter 2.5
    DOI:  https://doi.org/10.1016/j.ecoenv.2024.116920
  6. bioRxiv. 2024 Aug 20. pii: 2024.08.19.608670. [Epub ahead of print]
    Topical ABT-263 treatment reduces aged skin senescence and improves subsequent wound healing.
    Maria Shvedova, Rex Jeya Rajkumar Samdavid Thanapaul, Joy Ha, Jannat Dhillon, Grace H Shin, Jack Crouch, Adam C Gower, Sami Gritli, Daniel S Roh.
      Senescent cells (SnC) accumulate in aging tissues, impairing their ability to undergo repair and regeneration following injury. Previous research has demonstrated that targeting tissue senescence with senolytics can enhance tissue regeneration and repair by selectively eliminating SnCs in specific aged tissues. In this study, we focused on eliminating SnC skin cells in aged mice to assess the effects on subsequent wound healing. We applied ABT-263 directly to the skin of 24-month-old mice over a 5-day period. Following topical ABT-263, aged skin demonstrated decreased gene expression of senescent markers p16 and p21, accompanied by reductions in SA-β-gal and p21-positive cells compared to DMSO controls. However, ABT-263 also triggered a temporary inflammatory response and macrophage infiltration in the skin. Bulk RNA sequencing of ABT-263-treated skin revealed prompt upregulation of genes associated with wound healing pathways, including hemostasis, inflammation, cell proliferation, angiogenesis, collagen synthesis, and extracellular matrix organization. Aged mice skin pre-treated with topical ABT-263 exhibited accelerated wound closure. In conclusion, topical ABT-263 effectively reduced several senescence markers in aged skin, thereby priming the skin for improved subsequent wound healing. This enhancement may be attributed to ABT-263-induced senolysis which in turn stimulates the expression of genes involved in extracellular matrix remodeling and wound repair pathways.
    DOI:  https://doi.org/10.1101/2024.08.19.608670
  7. Mol Neurobiol. 2024 Sep 04.
    The Potential of Mitochondrial Therapeutics in the Treatment of Oxidative Stress and Inflammation in Aging.
    Jitendra Kumar Sinha, Khanak Jorwal, Krishna Kumar Singh, Sung Soo Han, Rakesh Bhaskar, Shampa Ghosh.
      Mitochondria are central to cellular energy production, and their dysfunction is a major contributor to oxidative stress and chronic inflammation, pivotal factors in aging, and related diseases. With aging, mitochondrial efficiency declines, leading to an increase in ROS and persistent inflammatory responses. Therapeutic interventions targeting mitochondrial health show promise in mitigating these detrimental effects. Antioxidants such as MitoQ and MitoVitE, and supplements like coenzyme Q10 and NAD + precursors, have demonstrated potential in reducing oxidative stress. Additionally, gene therapy aimed at enhancing mitochondrial function, alongside lifestyle modifications such as regular exercise and caloric restriction can ameliorate age-related mitochondrial decline. Exercise not only boosts mitochondrial biogenesis but also improves mitophagy. Enhancing mitophagy is a key strategy to prevent the accumulation of dysfunctional mitochondria, which is crucial for cellular homeostasis and longevity. Pharmacological agents like sulforaphane, SS-31, and resveratrol indirectly promote mitochondrial biogenesis and improve cellular resistance to oxidative damage. The exploration of mitochondrial therapeutics, including emerging techniques like mitochondrial transplantation, offers significant avenues for extending health span and combating age-related diseases. However, translating these findings into clinical practice requires overcoming challenges in precisely targeting dysfunctional mitochondria and optimizing delivery mechanisms for therapeutic agents. Continued research is essential to refine these approaches and fully understand the interplay between mitochondrial dynamics and aging.
    Keywords:  Aging; Calorie restriction; Chronic inflammation; Mitochondrial biogenesis; Mitochondrial dysfunction; Oxidative stress
    DOI:  https://doi.org/10.1007/s12035-024-04474-0
  8. J Physiol Sci. 2024 Aug 31. 74(1): 40
    Role of the central nervous system in cell non-autonomous signaling mechanisms of aging and longevity in mammals.
    Takuya Urushihata, Akiko Satoh.
      Multiple organs orchestrate the maintenance of proper physiological function in organisms throughout their lifetimes. Recent studies have uncovered that aging and longevity are regulated by cell non-autonomous signaling mechanisms in several organisms. In the brain, particularly in the hypothalamus, aging and longevity are regulated by such cell non-autonomous signaling mechanisms. Several hypothalamic neurons have been identified as regulators of mammalian longevity, and manipulating them promotes lifespan extension or shortens the lifespan in rodent models. The hypothalamic structure and function are evolutionally highly conserved across species. Thus, elucidation of hypothalamic function during the aging process will shed some light on the mechanisms of aging and longevity and, thereby benefiting to human health.
    Keywords:  Aging; Cell non-autonomous; Cross-species comparison; Hypothalamus; Longevity; Sleep
    DOI:  https://doi.org/10.1186/s12576-024-00934-3
  9. Nat Aging. 2024 Aug 29.
    Ribosomal S6 kinase 1 regulates inflammaging via the senescence secretome.
    Suchira Gallage, Elaine E Irvine, Jose Efren Barragan Avila, Virinder Reen, Silvia M A Pedroni, Imanol Duran, Vikas Ranvir, Sanjay Khadayate, Joaquim Pombo, Sharon Brookes, Danijela Heide, Gopuraja Dharmalingham, Agharul I Choudhury, Indrabahadur Singh, Nicolás Herranz, Santiago Vernia, Mathias Heikenwalder, Jesús Gil, Dominic J Withers.
      Inhibition of S6 kinase 1 (S6K1) extends lifespan and improves healthspan in mice, but the underlying mechanisms are unclear. Cellular senescence is a stable growth arrest accompanied by an inflammatory senescence-associated secretory phenotype (SASP). Cellular senescence and SASP-mediated chronic inflammation contribute to age-related pathology, but the specific role of S6K1 has not been determined. Here we show that S6K1 deletion does not reduce senescence but ameliorates inflammation in aged mouse livers. Using human and mouse models of senescence, we demonstrate that reduced inflammation is a liver-intrinsic effect associated with S6K deletion. Specifically, we show that S6K1 deletion results in reduced IRF3 activation; impaired production of cytokines, such as IL1β; and reduced immune infiltration. Using either liver-specific or myeloid-specific S6K knockout mice, we also demonstrate that reduced immune infiltration and clearance of senescent cells is a hepatocyte-intrinsic phenomenon. Overall, deletion of S6K reduces inflammation in the liver, suggesting that suppression of the inflammatory SASP by loss of S6K could underlie the beneficial effects of inhibiting this pathway on healthspan and lifespan.
    DOI:  https://doi.org/10.1038/s43587-024-00695-z
  10. medRxiv. 2024 Jul 24. pii: 2024.07.23.24310854. [Epub ahead of print]
    Polygenic proxies of age-related plasma protein levels reveal TIMP2 role in cognitive performance.
    Federica Anastasi, Patricia Genius, Blanca Rodriguez-Fernandez, Chengran Yang, Priyanka Gorijala, Jigyasha Timsina, Felipe Hernández-Villamizar, Luigi Lorenzini, Marta Del Campo, Gonzalo Sánchez-Benavides, Carolina Minguillon, Arcadi Navarro, Carlos Cruchaga, Marc Suárez-Calvet, Natalia Vilor-Tejedor.
      Several studies have identified blood proteins that influence brain aging performance in mice, yet translating these findings to humans remains challenging. Here we found that higher predicted plasma levels of Tissue Inhibitor of Metalloproteinases 2 (TIMP2) were significantly associated with improved global cognition and memory performance in humans. We first identified 12 proteins with aging or rejuvenating effects on murine brains through a systematic review. Using protein quantitative trait loci data for these proteins, we computed polygenic scores as proxies for plasma protein levels and validated their prediction accuracy in two independent cohorts. Association models between genetic proxies and cognitive performance highlighted the significance of TIMP2, also when the models were stratified by sex, APOE -ε4, and Aβ42 status. This finding aligns with TIMP2's brain-rejuvenating role in murine models, suggesting it as a promising therapeutic target for brain aging and age-related brain diseases in humans.
    DOI:  https://doi.org/10.1101/2024.07.23.24310854
  11. Food Funct. 2024 Sep 03.
    Lycium barbarum berry extract improves female fertility against aging-related oxidative stress in the ovary.
    Chenyu Jiang, Ziyu Chen, Haoming Xiong, Xiao Yang, Weilin Liao, Geer Chen, Chen Huang, Guoyuan Zhu, Haijie Yu, Lijuan Ma.
      Reproductive aging in female mammals is characterized by ovarian senescence, leading to a significant fertility decline. Lycium barbarum berry, or goji berry, is a food and medicine that appears in various formulas for treating infertility in traditional Chinese medicine. We investigated the function of an aqueous extract of Lycium barbarum berry (LB extract) to improve health status, fertility, and offspring development during female aging. Aged female mice were supplemented with LB extract, and its effects on fertility, locomotor activity, and offspring development were assessed. The results demonstrated that LB extract significantly increased pregnancy and live birth rates in naturally aged female mice. It also effectively improved aged animals' locomotor activity. Moreover, LB extract promoted the growth and development of offspring delivered from the aged animals and reduced the offspring's anxiety. During aging, fertility-related hormones gradually decline. However, the decline of anti-Müllerian hormone (AMH) and estradiol (E2) in the serum of aged mice was restored by LB extract supplementation. Immunohistochemical analysis revealed that the levels of oxidation and the inflammatory IL-6 in intra-ovarian cells were reduced by LB extract, while the antioxidant-associated proteins peroxiredoxin 4 (PRDX4) and nuclear factor erythroid 2-related factor 2 (NRF2) were increased. Bioinformatics analysis revealed a decline in egg PRDX4 expression with age across various species. This suggests that the antioxidant function protected by LB extract through PRDX4 may consistently promote fertility enhancement by improving ovarian function across different species. Importantly, LB extract did not induce significant adverse effects on aged female mice and their offspring. These findings highlight the potential of LB as a protective agent against ovarian oxidative stress, which preserves ovarian function and improves fertility rates in naturally senescent females.
    DOI:  https://doi.org/10.1039/d4fo02720e
  12. Life Sci. 2024 Sep 03. pii: S0024-3205(24)00624-6. [Epub ahead of print] 123034
    Nerol mitigates dexamethasone-induced skin aging by activating the Nrf2 signaling pathway in human dermal fibroblasts.
    Wesuk Kang, Yoojeong Ha, Yearim Jung, Hyunbin Lee, Taesun Park.
      Collagen and hyaluronic acid are essential components of the dermis that collaborate to maintain skin elasticity and hydration due to their unique biochemical properties and interactions within the extracellular matrix. Prolonged exposure to glucocorticoids can induce skin aging, which manifests as diminished collagen content and hyaluronic acid levels in the dermis. Nerol, a monoterpene alcohol found in essential oils, was examined in this study for its potential to counteract glucocorticoid-induced skin aging and the underlying mechanism behind its effects. Our findings reveal that non-toxic concentrations of nerol treatment can reinstate collagen content and hyaluronic acid levels in human dermal fibroblasts treated with dexamethasone. Mechanistically, nerol mitigates dexamethasone-induced oxidative stress by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. The protective effects of nerol were significantly abrogated when the Nrf2 pathway was inhibited using the specific inhibitor ML385. In conclusion, nerol protects human dermal fibroblasts against glucocorticoid-induced skin aging by ameliorating oxidative stress via activation of the Nrf2 pathway, thereby highlighting its potential as a therapeutic agent for preventing and treating glucocorticoid-induced skin aging.
    Keywords:  Collagen; Dermal fibroblasts; Glucocorticoid; Nerol; Nrf2
    DOI:  https://doi.org/10.1016/j.lfs.2024.123034
  13. Aging Dis. 2024 Aug 22.
    Mitochondria-Associated Membranes in Aging and Senescence.
    Zhaojia Wang, Xiao Du, Shiran Yu, Xuzhen Yan, Yanguo Xin.
      Although the pursuit of eternal youth remains elusive, progress in the fields of medicine and science has greatly extended the human lifespan. Nevertheless, the rising incidence of diseases and their economic impact present notable obstacles. Mitochondria-associated membranes (MAMs), essential sites for close interaction between mitochondria and the endoplasmic reticulum (ER), are increasingly recognized for their involvement in both normal cellular processes and the development of diseases. Studies suggest that MAMs undergo dynamic alterations, particularly pertinent in the investigation of age-related illnesses. This review highlights the significance of MAMs in age-related conditions, elucidating the morphological and functional alterations in mitochondria and ER during aging. By emphasizing the complex interaction between these organelles, it demonstrates the cell's adaptive responses to combat age-related deterioration. Suggesting MAMs as potential targets for therapeutic interventions holds the potential for attenuating the progression of age-related diseases.
    DOI:  https://doi.org/10.14336/AD.2024.0652
  14. Geroscience. 2024 Sep 02.
    Effect of aging and exercise on hTERT expression in thymus tissue of hTERT transgenic bacterial artificial chromosome mice.
    Jeongjin J Kim, Alexander Ahn, Jeffrey Y Ying, Jesse Pollens-Voigt, Andrew T Ludlow.
      Telomere shortening occurs with aging in immune cells and may be related to immunosenescence. Exercise can upregulate telomerase activity and attenuate telomere shortening in immune cells, but it is unknown if exercise impacts other immune tissues such as the thymus. This study aimed to examine human telomerase reverse transcriptase (hTERT) alternative splicing (AS) in response to aging and exercise in thymus tissue. Transgenic mice with a human TERT bacterial artificial chromosome integrated into its genome (hTERT-BAC) were utilized in two different exercise models. Mice of different ages were assigned to an exercise cage (running wheel) or not for 3 weeks prior to thymus tissue excision. Middle-aged mice (16 months) were exposed or not to treadmill running (30 min at 60% maximum speed) prior to thymus collection. hTERT transcript variants were measured by RT-PCR. hTERT transcripts decreased with aging (r =  - 0.7511, p < 0.0001) and 3 weeks of wheel running did not counteract this reduction. The ratio of exons 7/8 containing hTERT to total hTERT transcripts increased with aging (r = 0.3669, p = 0.0423) but 3 weeks of voluntary wheel running attenuated this aging-driven effect (r = 0.2013, p = 0.4719). Aging increased the expression of senescence marker p16 with no impact of wheel running. Thymus regeneration transcription factor, Foxn1, went down with age with no impact of wheel running exercise. Acute treadmill exercise did not induce any significant changes in thymus hTERT expression or AS variant ratio (p > 0.05). In summary, thymic hTERT expression is reduced with aging. Exercise counteracted a shift in hTERT AS ratio with age. Our data demonstrate that aging impacts telomerase expression and that exercise impacts dysregulated splicing that occurs with aging.
    Keywords:  Aging; Alternative splicing; TERT; Telomerase; Thymus
    DOI:  https://doi.org/10.1007/s11357-024-01319-5
  15. Cell Metab. 2024 Sep 03. pii: S1550-4131(24)00330-9. [Epub ahead of print]36(9): 1911-1913
    Defying "IL-11ness" by inhibiting inflammation: Strategy for health and longevity.
    Hee-Hoon Kim, Vishwa Deep Dixit.
      Organismal aging involves several hallmark pathways, including chronic inflammation and metabolic dysfunction. However, the origin of age-related inflammation is incompletely understood. In a recent study published in Nature,1 Widjaja et al. show that blocking the age-related increase in IL-11 restores immune-metabolic homeostasis and extends healthspan and lifespan in mice.
    DOI:  https://doi.org/10.1016/j.cmet.2024.08.003
  16. ACS Biomater Sci Eng. 2024 Sep 03.
    Bone Tissue Engineering with Adipose-Derived Stem Cells in Polycaprolactone/Graphene Oxide/Dexamethasone 3D-Printed Scaffolds.
    Chih-Hao Chen, Banendu Sunder Dash, Wei-Chun Ting, Jyh-Ping Chen.
      We fabricated three-dimensional (3D)-printed polycaprolactone (PCL) and PCL/graphene oxide (GO) (PGO) scaffolds for bone tissue engineering. An anti-inflammatory and pro-osteogenesis drug dexamethasone (DEX) was adsorbed onto GO and a 3D-printed PGO/DEX (PGOD) scaffold successfully improved drug delivery with a sustained release of DEX from the scaffold up to 1 month. The physicochemical properties of the PCL, PGO, and PGOD scaffolds were characterized by various analytical techniques. The biological response of these scaffolds was studied for adherence, proliferation, and osteogenic differentiation of seeded rabbit adipose-derived stem cells (ASCs) from DNA assays, alkaline phosphatase (ALP) production, calcium quantification, osteogenic gene expression, and immunofluorescence staining of osteogenic marker proteins. The PGOD scaffold was demonstrated to be the best scaffold for maintaining cell viability, cell proliferation, and osteogenic differentiation of ASCs in vitro. In vivo biocompatibility of PGOD was confirmed from subcutaneous implantation in nude mice where ASC-seeded PGOD can form ectopic bones, demonstrated by microcomputed tomography (micro-CT) analysis and immunofluorescence staining. Furthermore, implantation of PGOD/ASCs constructs into critical-sized cranial bone defects in rabbits form tissue-engineered bones at the defect site, observed using micro-CT and histological analysis.
    Keywords:  3D-printed scaffold; adipose-derived stem cell; bone tissue engineering; dexamethasone; graphene oxide
    DOI:  https://doi.org/10.1021/acsbiomaterials.4c00774
  17. Acta Biochim Biophys Sin (Shanghai). 2024 Aug 15. 56(8): 1208-1220
    Glycosylation in aging and neurodegenerative diseases.
    Weilong Zhang, Tian Chen, Huijuan Zhao, Shifang Ren.
      Aging, a complex biological process, involves the progressive decline of physiological functions across various systems, leading to increased susceptibility to neurodegenerative diseases. In society, demographic aging imposes significant economic and social burdens due to these conditions. This review specifically examines the association of protein glycosylation with aging and neurodegenerative diseases. Glycosylation, a critical post-translational modification, influences numerous aspects of protein function that are pivotal in aging and the pathophysiology of diseases such as Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions. We highlight the alterations in glycosylation patterns observed during aging, their implications in the onset and progression of neurodegenerative diseases, and the potential of glycosylation profiles as biomarkers for early detection, prognosis, and monitoring of these age-associated conditions, and delve into the mechanisms of glycosylation. Furthermore, this review explores their role in regulating protein function and mediating critical biological interactions in these diseases. By examining the changes in glycosylation profiles associated with each part, this review underscores the potential of glycosylation research as a tool to enhance our understanding of aging and its related diseases.
    Keywords:  aging; glycosylation; neurodegenerative diseases
    DOI:  https://doi.org/10.3724/abbs.2024136
  18. Geriatr Gerontol Int. 2024 Sep 03.
    Allostatic load in rat model: An efficient tool for evaluating and understanding aging.
    Dandan Chen, Xiaohong Deng, Yuxin Jia, Xianjun Sun, Xiaohong Duan, Shikai Yan, Jianhua Huang.
       AIM: Aging and age-related diseases are an ever-increasing social and public health problem. Allostatic load (AL) shows great potential as an interdisciplinary tool for assessing the aging of human beings but as yet lacks investigation in animal models which is our study focus at.
    METHODS: Here a continuous study of AL was conducted on naturally aging rats. Blood samples were collected from the rats at ages of 5, 8, 14, 18, and 21 months. Dozens of blood biochemical indicators, including serum corticosterone, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, C-reactive protein, interleukin-6, 25-hydroxyvitamin D, free fatty acid, CD3+ T cell count, CD4+/CD3+ T cell ratio, CD8+/CD3+ T cell ratio, and CD3/4/8+ T cell apoptosis, were determined.
    RESULTS: AL was scored from those indicators, and we found that AL score gradually increased with age.
    CONCLUSIONS: AL can reliably reveal the cumulative and systemic changes in aging. Geriatr Gerontol Int 2024; ••: ••-••.
    Keywords:  aging; allostatic load; immunity
    DOI:  https://doi.org/10.1111/ggi.14950
  19. Adv Mater. 2024 Sep 02. e2408678
    Sequential Targeted Enzyme-Instructed Self-Assembly Supramolecular Nanofibers to Attenuate Intervertebral Disc Degeneration.
    Yang Liu, Xun Sun, Lianlei Wang, Yiming Dou, Ye Tian, Tianyu Yu, Yiming Zhang, Qingqian Zhao, Jiayi Lu, Yinyin Feng, Jiayu Wang, Xinyu Liu, Yuna Shang, Chunju Li, Qiang Yang.
      As an age-related disease, intervertebral disc degeneration is closely related to inflammation and aging. Inflammatory cytokines and cellular senescence collectively contribute to the degradation of intervertebral disc. Blocking this synergy reduces disc extracellular matrix damage caused by inflammation and aging. In this study, drug-loaded nanofibers with sequential targeting functions are constructed through intelligent response, hydrophilicity, and in situ self-assembly empowerment of flurbiprofen. The peptide precursor responds to the cleavage of overexpressed MMP-2 in the degenerative intervertebral disc microenvironment (intracellular and extracellular), resulting in the formation of self-assembled nanofibers that enable the on-demand release of flurbiprofen and COX-2 response. In vitro, Comp. 1 (Flurbiprofen-GFFYPLGLAGEEEERGD) reduces the expression of inflammation-related genes and proteins and the polarization of M1 macrophages by competitively inhibiting COX-2 and increases the expression of extracellular matrix proteins COL-2 and aggrecan. Additionally, it can reduce the expression of Senescence-Associated Secretory Phenotype and DNA damage in aged nucleus pulposus cells and promote the recovery of proliferation and cell cycle. In vivo, drug-loaded nanofibers delay intervertebral disc degeneration by inhibiting inflammation and preventing the accumulation of senescent cells. Therefore, the sequentially targeted self-assembled drug-loaded nanofibers can delay intervertebral disc degeneration by blocking the synergistic effect of inflammatory cytokines and cellular senescence.
    Keywords:  cellular senescence; enzyme‐instructed self‐assembly; inflammation; intervertebral disc degeneration; nanofiber
    DOI:  https://doi.org/10.1002/adma.202408678
  20. Front Pharmacol. 2024 ;15 1386604
    Barleriside A, an aryl hydrocarbon receptor antagonist, ameliorates podocyte injury through inhibiting oxidative stress and inflammation.
    Xiao-Jun Li, Yan-Ni Wang, Wen-Feng Wang, Xiaoli Nie, Hua Miao, Ying-Yong Zhao.
       Introduction: Increasing evidence shows that hyperactive aryl hydrocarbon receptor (AHR) signalling is involved in renal disease. However, no currently available intervention strategy is effective in halting disease progression by targeting the AHR signalling. Our previous study showed that barleriside A (BSA), a major component of Plantaginis semen, exhibits renoprotective effects.
    Methods: In this study, we determined the effects of BSA on AHR expression in 5/6 nephrectomized (NX) rats. We further determined the effect of BSA on AHR, nuclear factor kappa B (NF-ƙB), and the nuclear factor erythroid 2-related factor 2 (Nrf2) signalling cascade in zymosan-activated serum (ZAS)-stimulated MPC5 cells.
    Results: BSA treatment improved renal function and inhibited intrarenal nuclear AHR protein expression in NX-treated rats. BSA mitigated podocyte lesions and suppressed AHR mRNA and protein expression in ZAS-stimulated MPC5 cells. BSA inhibited inflammation by improving the NF-ƙB and Nrf2 pathways in ZAS-stimulated MPC5 cells. However, BSA did not markedly upregulate the expression of podocyte-specific proteins in the ZAS-mediated MPC5 cells treated with CH223191 or AHR siRNA compared to untreated ZAS-induced MPC5 cells. Similarly, the inhibitory effects of BSA on nuclear NF-ƙB p65, Nrf2, and AHR, as well as cytoplasmic cyclooxygenase-2, heme oxygenase-1, and AHR, were partially abolished in ZAS-induced MPC5 cells treated with CH223191 or AHRsiRNA compared with untreated ZAS-induced MPC5 cells. These results indicated that BSA attenuated the inflammatory response, partly by inhibiting AHR signalling.
    Discussion: Both pharmacological and siNRA findings suggested that BSA mitigated podocyte lesions by improving the NF-ƙB and Nrf2 pathways via inhibiting AHR signalling. Therefore, BSA is a high-affinity AHR antagonist that abolishes oxidative stress and inflammation.
    Keywords:   oxidative stress and inflammation; Nrf2; Plantaginis semen; aryl hydrocarbon receptor; barleriside A; chronic kidney disease; nuclear factor kappa B; podocyte injury
    DOI:  https://doi.org/10.3389/fphar.2024.1386604
  21. Ageing Res Rev. 2024 Aug 31. pii: S1568-1637(24)00293-9. [Epub ahead of print] 102475
    Potential implications of natural compounds on aging and metabolic regulation.
    Zhuozhen Li, Lili Chen, Liangliang Qu, Wenjie Yu, Tao Liu, Fangjian Ning, Jinwang Li, Xiali Guo, Fengjie Sun, Baoguo Sun, Liping Luo.
      Aging is generally accompanied by a progressive loss of metabolic homeostasis. Targeting metabolic processes is an attractive strategy for healthy-aging. Numerous natural compounds have demonstrated strong anti-aging effects. This review summarizes recent findings on metabolic pathways involved in aging and explores the anti-aging effects of natural compounds by modulating these pathways. The potential anti-aging effects of natural extracts rich in biologically active compounds are also discussed. Regulating the metabolism of carbohydrates, proteins, lipids, and nicotinamide adenine dinucleotide is an important strategy for delaying aging. Furthermore, phenolic compounds, terpenoids, alkaloids, and nucleotide compounds have shown particularly promising effects on aging, especially with respect to metabolism regulation. Moreover, metabolomics is a valuable tool for uncovering potential targets against aging. Future research should focus on identifying novel natural compounds that regulate human metabolism and should delve deeper into the mechanisms of metabolic regulation using metabolomics methods, aiming to delay aging and extend lifespan.
    Keywords:  Natural compound; aging; anti-aging; metabolism; metabolomics
    DOI:  https://doi.org/10.1016/j.arr.2024.102475
  22. Biochemistry (Mosc). 2024 Jul;89(7): 1183-1191
    Use of qPCR to Evaluate Efficiency of the Bulky DNA Damage Removal in Extracts of Mammalian Cells with Different Maximum Lifespan.
    Aleksei A Popov, Vladimir A Shamanin, Irina O Petruseva, Aleksei N Evdokimov, Olga I Lavrik.
      Proteins of nucleotide excision repair system (NER) are responsible for detecting and removing a wide range of bulky DNA damages, thereby contributing significantly to the genome stability maintenance within mammalian cells. Evaluation of NER functional status in the cells is important for identifying pathological changes in the body and assessing effectiveness of chemotherapy. The following method, described herein, has been developed for better assessment of bulky DNA damages removal in vitro, based on qPCR. Using the developed method, NER activity was compared for the extracts of the cells from two mammals with different lifespans: a long-lived naked mole-rat (Heterocephalus glaber) and a short-lived mouse (Mus musculus). Proteins of the H. glaber cell extract have been shown to be 1.5 times more effective at removing bulky damage from the model DNA substrate than the proteins of the M. musculus cell extract. These results are consistent with the experimental data previously obtained. The presented method could be applied not only in fundamental studies of DNA repair in mammalian cells, but also in clinical practice.
    Keywords:  DNA repair; PCR; longevity
    DOI:  https://doi.org/10.1134/S0006297924070022
  23. Nat Aging. 2024 Sep 03.
    Loss of coordination between basic cellular processes in human aging.
    Ana Carolina Leote, Francisco Lopes, Andreas Beyer.
      Age-related loss of gene expression coordination has been reported for distinct cell types and may lead to impaired cellular function. Here we propose a method for quantifying age-related changes in transcriptional regulatory relationships between genes, based on a model learned from external data. We used this method to uncover age-related trends in gene-gene relationships across eight human tissues, which demonstrates that reduced co-expression may also result from coordinated transcriptional responses. Our analyses reveal similar numbers of strengthening and weakening gene-gene relationships with age, impacting both tissue-specific (for example, coagulation in blood) and ubiquitous biological functions. Regulatory relationships becoming weaker with age were established mostly between genes operating in distinct cellular processes. As opposed to that, regulatory relationships becoming stronger with age were established both within and between different cellular functions. Our work reveals that, although most transcriptional regulatory gene-gene relationships are maintained during aging, those with declining regulatory coupling result mostly from a loss of coordination between distinct cellular processes.
    DOI:  https://doi.org/10.1038/s43587-024-00696-y
  24. Aging Cell. 2024 Aug 29. e14327
    Periodic protein-restricted diets extend the lifespan of high-fat diet-induced Drosophila melanogaster males.
    Ruohua Wang, Qiushuang Zhu, He Huang, Mengxia Yang, Xinyue Wang, Yuanjie Dong, Yuqiao Li, Yue Guan, Lei Zhong, Yucun Niu.
      Research has shown that sustained protein restriction can improve the effects of a high-fat diet on health and extend lifespan. However, long-term adherence to a protein-restricted diet is challenging. Therefore, we used a fly model to investigate whether periodic protein restriction (PPR) could also mitigate the potential adverse effects of a high-fat diet and extend healthy lifespan. Our study results showed that PPR reduced body weight, lipid levels, and oxidative stress induced by a high-fat diet in flies and significantly extended the healthy lifespan of male flies. Lipid metabolism and transcriptome results revealed that the common differences between the PPR group and the control group and high-fat group showed a significant decrease in palmitic acid in the PPR group; the enriched common differential pathways Toll and Imd were significantly inhibited in the PPR group. Further analysis indicated a significant positive correlation between palmitic acid levels and gene expression in the Toll and Imd pathways. This suggests that PPR effectively improves fruit fly lipid metabolism, reduces palmitic acid levels, and thereby suppresses the Toll and Imd pathways to extend the healthy lifespan of flies. Our study provides a theoretical basis for the long-term effects of PPR on health and offers a new dietary adjustment option for maintaining health in the long term.
    Keywords:  dietary adjustments; fatty acid metabolism; high‐fat diet; lifespan; periodic protein‐restricted diet
    DOI:  https://doi.org/10.1111/acel.14327
  25. Chembiochem. 2024 Sep 06. e202400529
    HPPE Activates NRF2 Signaling by Liberating Heavy Metal Stores.
    Rebecca Freeman, Michael Bollong.
      The Cap'n'collar transcription factor BACH1 represses the transcription of gene products involved in oxidative stress protection. Accordingly, agents capable of inhibiting the activity of BACH1 would be of keen interest in treating several autoimmune and age-related diseases. Here, we report that a previously annotated BACH1 inhibitor, HPPE, does not inhibit BACH1 but instead activates a NRF2 driven transcription program that is dependent on the canonical cysteine sensors of NRF2 inhibitory protein KEAP1. Mechanistically, HPPE acts as an ionophore, liberating cellular Zn2+ stores and inducing non-lethal levels of reactive oxygen species, resulting in KEAP1 inactivation. These data provide a surprising mechanism by which HPPE acts in cells and suggest that inducing small amounts of cellular stress may be a viable mechanism for activating NRF2 therapeutically.
    Keywords:  NRF2 HPPE oxidative stress
    DOI:  https://doi.org/10.1002/cbic.202400529
  26. World Neurosurg. 2024 Sep 02. pii: S1878-8750(24)01428-1. [Epub ahead of print]
    Cellular Senescence in Diffuse Gliomas: From Physiopathology to Possible Treatments.
    Edgar G Ordóñez-Rubiano, Alba Cómbita, Matías Baldoncini, César Payán-Gómez, Diego F Gómez-Amarillo, Fernando Hakim, Julián Camargo, Valentina Zorro-Sepúlveda, Sabino Luzzi, Oscar Zorro, Rafael Parra- Medina.
      Cellular senescence in gliomas is a complex process that is induced by aging and replication, ionizing radiation, oncogenic stress, and the use of temozolomide. However, the escape routes that gliomas must evade senescence and achieve cellular immortality are much more complex, in which the expression of telomerase and the alternative lengthening of telomeres, as well as the mutation of some proto-oncogenes or tumor suppressor genes, are involved. In gliomas, these molecular mechanisms related to cellular senescence can have a tumor-suppressing or promoting effect and are directly involved in tumor recurrence and progression. From these cellular mechanisms related to cellular senescence, it is possible to generate targeted senostatic and senolytic therapies that improve the response to currently available treatments and improve survival rates. This review aims to summarize the mechanisms of induction and evasion of cellular senescence in gliomas, as well as review possible treatments with therapies targeting pathways related to cellular senescence.
    Keywords:  cellular senescence; diffuse glioma; glioblastoma; glioma; molecular pathology; senescence
    DOI:  https://doi.org/10.1016/j.wneu.2024.08.060
  27. Sci China Life Sci. 2024 Sep 02.
    An in-depth understanding of the role and mechanisms of T cells in immune organ aging and age-related diseases.
    Yudai Xu, Zijian Wang, Shumin Li, Jun Su, Lijuan Gao, Junwen Ou, Zhanyi Lin, Oscar Junhong Luo, Chanchan Xiao, Guobing Chen.
      T cells play a critical and irreplaceable role in maintaining overall health. However, their functions undergo alterations as individuals age. It is of utmost importance to comprehend the specific characteristics of T-cell aging, as this knowledge is crucial for gaining deeper insights into the pathogenesis of aging-related diseases and developing effective therapeutic strategies. In this review, we have thoroughly examined the existing studies on the characteristics of immune organ aging. Furthermore, we elucidated the changes and potential mechanisms that occur in T cells during the aging process. Additionally, we have discussed the latest research advancements pertaining to T-cell aging-related diseases. These findings provide a fresh perspective for the study of T cells in the context of aging.
    Keywords:  T cell; age-related diseases; aging; immune organ
    DOI:  https://doi.org/10.1007/s11427-024-2695-x
  28. Cancer Metastasis Rev. 2024 Sep 06.
    Multifaceted role of the DNA replication protein MCM10 in maintaining genome stability and its implication in human diseases.
    Sumayyah M Q Ahmed, Jayaprakash Sasikumar, Suparna Laha, Shankar Prasad Das.
      MCM10 plays a vital role in genome duplication and is crucial for DNA replication initiation, elongation, and termination. It coordinates several proteins to assemble at the fork, form a functional replisome, trigger origin unwinding, and stabilize the replication bubble. MCM10 overexpression is associated with increased aggressiveness in breast, cervical, and several other cancers. Disruption of MCM10 leads to altered replication timing associated with initiation site gains and losses accompanied by genome instability. Knockdown of MCM10 affects the proliferation and migration of cancer cells, manifested by DNA damage and replication fork arrest, and has recently been shown to be associated with clinical conditions like CNKD and RCM. Loss of MCM10 function is associated with impaired telomerase activity, leading to the accumulation of abnormal replication forks and compromised telomere length. MCM10 interacts with histones, aids in nucleosome assembly, binds BRCA2 to maintain genome integrity during DNA damage, prevents lesion skipping, and inhibits PRIMPOL-mediated repriming. It also interacts with the fork reversal enzyme SMARCAL1 and inhibits fork regression. Additionally, MCM10 undergoes several post-translational modifications and contributes to transcriptional silencing by interacting with the SIR proteins. This review explores the mechanism associated with MCM10's multifaceted role in DNA replication initiation, chromatin organization, transcriptional silencing, replication stress, fork stability, telomere length maintenance, and DNA damage response. Finally, we discuss the role of MCM10 in the early detection of cancer, its prognostic significance, and its potential use in therapeutics for cancer treatment.
    Keywords:  Cancer aggressiveness; Chromosomal instability; MCM10; Replication initiation; Replication stress; Replication timing
    DOI:  https://doi.org/10.1007/s10555-024-10209-3
  29. Exp Mol Med. 2024 Sep 02.
    Telomere stabilization by metformin mitigates the progression of atherosclerosis via the AMPK-dependent p-PGC-1α pathway.
    Jin Young Sung, Seul Gi Kim, So-Young Park, Jae-Ryong Kim, Hyoung Chul Choi.
      Telomere dysfunction is a well-known molecular trigger of senescence and has been associated with various age-related diseases, including atherosclerosis. However, the mechanisms involved have not yet been elucidated, and the extent to which telomeres contribute to atherosclerosis is unknown. Therefore, we investigated the mechanism of metformin-induced telomere stabilization and the ability of metformin to inhibit vascular smooth muscle cell (VSMC) senescence caused by advanced atherosclerosis. The present study revealed that metformin inhibited the phenotypes of atherosclerosis and senescence in VSMCs. Metformin increased the phosphorylation of AMPK-dependent PGC-1α and thus increased telomerase activity and the protein level of TERT in OA-treated VSMCs. Mechanistically, the phosphorylation of AMPK and PGC-1α by metformin not only enhanced telomere function but also increased the protein level of TERT, whereas TERT knockdown accelerated the development of atherosclerosis and senescent phenotypes in OA-treated VSMCs regardless of metformin treatment. Furthermore, the in vivo results showed that metformin attenuated the formation of atherosclerotic plaque markers in the aortas of HFD-fed ApoE KO mice. Although metformin did not reduce plaque size, it inhibited the phosphorylation of the AMPK/PGC-1α/TERT signaling cascade, which is associated with the maintenance and progression of plaque formation, in HFD-fed ApoE KO mice. Accordingly, metformin inhibited atherosclerosis-associated phenotypes in vitro and in vivo. These observations show that the enhancement of telomere function by metformin is involved in specific signaling pathways during the progression of atherosclerosis. These findings suggest that telomere stabilization by metformin via the AMPK/p-PGC-1α pathway might provide a strategy for developing therapeutics against vascular diseases such as atherosclerosis.
    DOI:  https://doi.org/10.1038/s12276-024-01297-w
  30. Aging Cell. 2024 Sep 05. e14291
    Blockade of dopamine D3 receptors improves hippocampal synaptic function and rescues age-related cognitive phenotype.
    Maria Rosaria Tropea, Marcello Melone, Domenica Donatella Li Puma, Valeria Vacanti, Giuseppe Aceto, Bruno Bandiera, Roberta Carmela Trovato, Sebastiano Alfio Torrisi, Gian Marco Leggio, Agostino Palmeri, Marcello D'Ascenzo, Fiorenzo Conti, Claudio Grassi, Daniela Puzzo.
      Dopamine D3 receptors (D3Rs) modulate neuronal activity in several brain regions including the hippocampus. Although previous studies reported that blocking D3Rs exerts pro-cognitive effects, their involvement in hippocampal synaptic function and memory in the healthy and aged brain has not been thoroughly investigated. We demonstrated that in adult wild type (WT) mice, D3R pharmacological blockade or genetic deletion as in D3 knock out (KO) mice, converted the weak form of long-term potentiation (LTP1) into the stronger long-lasting LTP (LTP2) via the cAMP/PKA pathway, and allowed the formation of long-term memory. D3R effects were mainly mediated by post-synaptic mechanisms as their blockade enhanced basal synaptic transmission (BST), AMPAR-mediated currents, mEPSC amplitude, and the expression of the post-synaptic proteins PSD-95, phospho(p)GluA1 and p-CREB. Consistently, electron microscopy revealed a prevalent expression of D3Rs in post-synaptic dendrites. Interestingly, with age, D3Rs decreased in axon terminals while maintaining their levels in post-synaptic dendrites. Indeed, in aged WT mice, blocking D3Rs reversed the impairment of LTP, BST, memory, post-synaptic protein expression, and PSD length. Notably, aged D3-KO mice did not exhibit synaptic and memory deficits. In conclusion, we demonstrated the fundamental role of D3Rs in hippocampal synaptic function and memory, and their potential as a therapeutic target to counteract the age-related hippocampal cognitive decline.
    Keywords:  aging; dopamine D3 receptors; hippocampus; memory; synaptic plasticity
    DOI:  https://doi.org/10.1111/acel.14291
  31. Gerontologist. 2024 Sep 05. pii: gnae126. [Epub ahead of print]
    Finding the Balance to Quiet the Striving: The Difference Between Successful Aging and Wise Aging.
    Judith Glück, Luisa Jäger, Irina Auer-Spath, Imke Harbig.
      This paper draws on wisdom and lifespan development research to propose a conception of "wise aging", which may become particularly relevant in very old age as people's capacities for successful aging decline. We propose that three types of balance distinguish wise aging from successful aging. First, wisdom balances one's own interest with a greater good, emphasizing self-transcendence and compassion. Second, wisdom balances control striving with acceptance of uncontrollability. Wise aging involves a realistic awareness of one's decreasing levels of control and one's interconnectedness to and dependence on other people. Third, wisdom acknowledges, regulates, and balances positive and negative affect. Wise aging involves the ability to appreciate and relish the joys of life, but also to accept and embrace more negative emotions and fully support others going through different times.
    Keywords:  aging; self-transcendence; successful aging; wisdom; wise aging
    DOI:  https://doi.org/10.1093/geront/gnae126
  32. Aging Cell. 2024 Sep 05. e14324
    Rejuvenation of the reconstitution potential and reversal of myeloid bias of aged HSCs upon pH treatment.
    Sachin Kumar, Jeffrey D Vassallo, Kalpana J Nattamai, Aishlin Hassan, Angelika Vollmer, Rebekah Karns, Mehmet Sacma, Travis Nemkov, Angelo D'Alessandro, Hartmut Geiger.
      Aged hematopoietic stem cells (HSCs) show reduced reconstitution potential, limiting their use in transplantation settings in the clinic. We demonstrate here that exposure of aged HSCs ex vivo to a pH of 6.9 instead of the commonly used pH of 7.4 results in enhanced HSCs potential that is consistent with rejuvenation, including attenuation of the myeloid bias of aged HSC and restoration of a youthful frequency of epigenetic polarity. Rejuvenation of aged HSCs by pH 6.9 is, at least in part, due to alterations in the polyamine/methionine pathway within pH 6.9 HSCs, and consequently, attenuation of the production of spermidine also attenuated aging of HSCs. Exposure of aged HSCs to pH 6.9, or pharmacological targeting of the polyamine pathway, might thus extend the use of HSCs from aged donors for therapeutic applications.
    Keywords:  aging; hematopoietic stem cells; pH; polyamine; rejuvenation
    DOI:  https://doi.org/10.1111/acel.14324
  33. Aging Dis. 2024 Aug 18.
    Stress Hormones: Unveiling the Role in Accelerated Cellular Senescence.
    Tian Qin, Tao Chen, Rui Ma, Huan Li, Cui Li, Jin Zhao, Jinguo Yuan, Zuoming Zhang, Xiaoxuan Ning.
      Cellular senescence is a complex process involving multiple factors, such as genetics, environment, and behavior. However, recent studies have shown that stress also plays a crucial role in inducing cellular senescence. Stress can affect cellular function and structure through various pathways, leading to accelerated aging. Exposure to stressful conditions can alter the neuroendocrine system, activate the hypothalamus-pituitary-adrenal axis and sympathetic adrenal medullary axis, and release cortisol and catecholamines, causing mitochondrial dysfunction, generating excessive reactive oxygen species, and inducing oxidative stress, DNA damage, and inflammatory reactions, ultimately resulting in accelerated cellular senescence. The process of stress-induced cellular senescence has been implicated in a number of chronic diseases, including age-related macular degeneration, chronic kidney disease, type 2 diabetes, cardiovascular disease and obstructive sleep apnea. In this review, we integrate recent progress research progress in our understanding of the mechanisms of stress-induced cellular senescence and discuss its underlying mechanisms from the perspective of stress hormones. We review potential therapeutic targets for stress-induced premature senescence and discuss the advantages and limitations of existing pharmacological agents capable of ameliorating stress-induced premature senescence.
    DOI:  https://doi.org/10.14336/AD.2024.0262
  34. Autophagy. 2024 Aug 30.
    A surge in endogenous spermidine is essential for rapamycin-induced autophagy and longevity.
    Sebastian J Hofer, Ioanna Daskalaki, Mahmoud Abdellatif, Ulrich Stelzl, Simon Sedej, Nektarios Tavernarakis, Guido Kroemer, Frank Madeo.
      Acute nutrient deprivation (fasting) causes an immediate increase in spermidine biosynthesis in yeast, flies, mice and humans, as corroborated in four independent clinical studies. This fasting-induced surge in spermidine constitutes the critical first step of a phylogenetically conserved biochemical cascade that leads to spermidine-dependent hypusination of EIF5A (eukaryotic translation initiation factor 5A), which favors the translation of the pro-macroautophagic/autophagic TFEB (transcription factor EB), and hence an increase in autophagic flux. We observed that genetic or pharmacological inhibition of the spermidine increase by inhibition of ODC1 (ornithine decarboxylase 1) prevents the pro-autophagic and antiaging effects of fasting in yeast, nematodes, flies and mice. Moreover, knockout or knockdown of the enzymes required for EIF5A hypusination abolish fasting-mediated autophagy enhancement and longevity extension in these organisms. Of note, autophagy and longevity induced by rapamycin obey the same rule, meaning that they are tied to an increase in spermidine synthesis. These findings indicate that spermidine is not only a "caloric restriction mimetic" in the sense that its supplementation mimics the beneficial effects of nutrient deprivation on organismal health but that it is also an obligatory downstream effector of the antiaging effects of fasting and rapamycin.
    Keywords:  Aging; MTOR; autophagy; lifespan; rapamycin; spermidine
    DOI:  https://doi.org/10.1080/15548627.2024.2396793
  35. Biochemistry (Mosc). 2024 Jul;89(7): 1336-1348
    Differences in the Effect of Beta-Hydroxybutyrate on the Mitochondrial Biogenesis, Oxidative Stress and Inflammation Markers in Tissues from Young and Old Rats.
    Veronika V Nesterova, Polina I Babenkova, Anna A Brezgunova, Natalia A Samoylova, Irina S Sadovnikova, Dmitry S Semenovich, Nadezda V Andrianova, Artem P Gureev, Egor Y Plotnikov.
      One of the therapeutic approaches to age-related diseases is modulation of body cell metabolism through certain diets or their pharmacological mimetics. The ketogenic diet significantly affects cell energy metabolism and functioning of mitochondria, which has been actively studied in various age-related pathologies. Here, we investigated the effect of the ketogenic diet mimetic beta-hydroxybutyrate (BHB) on the expression of genes regulating mitochondrial biogenesis (Ppargc1a, Nrf1, Tfam), quality control (Sqstm1), functioning of the antioxidant system (Nfe2l2, Gpx1, Gpx3, Srxn1, Txnrd2, Slc6a9, Slc7a11), and inflammatory response (Il1b, Tnf, Ptgs2, Gfap) in the brain, lungs, heart, liver, kidneys, and muscles of young and old rats. We also analyzed mitochondrial DNA (mtDNA) copy number, accumulation of mtDNA damage, and levels of oxidative stress based on the concentration of reduced glutathione and thiobarbituric acid-reactive substances (TBARS). In some organs, aging disrupted mitochondrial biogenesis and functioning of cell antioxidant system, which was accompanied by the increased oxidative stress and inflammation. Administration of BHB for 2 weeks had different effects on the organs of young and old rats. In particular, BHB upregulated expression of genes coding for proteins associated with the mitochondrial biogenesis and antioxidant system, especially in the liver and muscles of young (but not old) rats. At the same time, BHB contributed to the reduction of TBARS in the kidneys of old rats. Therefore, our study has shown that administration of ketone bodies significantly affected gene expression in organs, especially in young rats, by promoting mitochondrial biogenesis, improving the functioning of the antioxidant defense system, and partially reducing the level of oxidative stress. However, these changes were much less pronounced in old animals.
    Keywords:  aging; beta-hydroxybutyrate; ketogenic diet; mitochondria; mitochondrial DNA; oxidative stress
    DOI:  https://doi.org/10.1134/S0006297924070149
  36. JBMR Plus. 2024 Oct;8(10): ziae101
    IL-33 prevents age-related bone loss and memory impairment by suppression of Th17 response: evidence in a d-galactose-induced aging mouse model.
    Saurabh Kumar Kaushal, Parul, Alok Tripathi, Devendra Pratap Singh, Ankita Paul, Kumari Alka, Shubha Shukla, Divya Singh.
      Cytokines are the primary mediators of age-related disorders. The IL-17/IL-10 axis plays a crucial role in bone destruction and neuro-inflammation. Additionally, a new Th2 cytokine-IL-33-has gained attention for its potential implications in aging-associated conditions. However, the involvement of IL-33 in aging-mediated bone loss and memory impairment remains unclear and needs further investigation. This study reveals the impact of IL-33 on various aspects of the immune system, bone health, and neural functions. To induce senescence, we used d-galactose for its convenience and fewer side effects. The experimental design involved treating 20-week-old C57BL/6J mice with d-galactose subcutaneously for 10 weeks to induce aging-like effects. Thereafter, IL-33 recombinant protein was administered intraperitoneally for 15 days to evaluate its impact on various immune, skeletal, and neural parameters. The results demonstrated that d-galactose-induced aging led to bone loss and compromised osteogenic parameters, accompanied by increased oxidative stress and neurodegeneration in specific brain regions. Behavioral activities were also affected. However, supplementation with IL-33 mitigated these effects, elevating osteogenic parameters and reducing senescence markers in osteoblast cells in an aging mouse model and exerted neuroprotective potential. Notably d-galactose-induced aging was characterized by high bone turnover, reflected by altered serum levels of CTX, PTH, beta-galactosidase, and P1NP. IL-33 treatment attenuated these effects, suggesting its role in regulating bone metabolism. Furthermore, d-galactose-induced aging was associated with increased differentiation of Th17 cells and upregulation of associated markers, such as STAT-3 and ROR-γt, while downregulating Foxp3, which antagonizes Th17 cell differentiation. IL-33 treatment countered these effects by suppressing Th17 cell differentiation and promoting IL-10-producing T-regulatory cells. Overall, these findings provide insights into the potential therapeutic implications of IL-33 in addressing aging-induced bone loss and memory impairment.
    Keywords:  T cells; aging; immune system; inflammation; oxidative stress
    DOI:  https://doi.org/10.1093/jbmrpl/ziae101
  37. Nucleic Acids Res. 2024 Sep 04. pii: gkae757. [Epub ahead of print]
    DNA methylation by CcrM contributes to genome maintenance in the Agrobacterium tumefaciens plant pathogen.
    Sandra Martin, Florian Fournes, Giovanna Ambrosini, Christian Iseli, Karolina Bojkowska, Julien Marquis, Nicolas Guex, Justine Collier.
      The cell cycle-regulated DNA methyltransferase CcrM is conserved in most Alphaproteobacteria, but its role in bacteria with complex or multicentric genomes remains unexplored. Here, we compare the methylome, the transcriptome and the phenotypes of wild-type and CcrM-depleted Agrobacterium tumefaciens cells with a dicentric chromosome with two essential replication origins. We find that DNA methylation has a pleiotropic impact on motility, biofilm formation and viability. Remarkably, CcrM promotes the expression of the repABCCh2 operon, encoding proteins required for replication initiation/partitioning at ori2, and represses gcrA, encoding a conserved global cell cycle regulator. Imaging ori1 and ori2 in live cells, we show that replication from ori2 is often delayed in cells with a hypo-methylated genome, while ori2 over-initiates in cells with a hyper-methylated genome. Further analyses show that GcrA promotes the expression of the RepCCh2 initiator, most likely through the repression of a RepECh2 anti-sense RNA. Altogether, we propose that replication at ori1 leads to a transient hemi-methylation and activation of the gcrA promoter, allowing repCCh2 activation by GcrA and contributing to initiation at ori2. This study then uncovers a novel and original connection between CcrM-dependent DNA methylation, a conserved epigenetic regulator and genome maintenance in an Alphaproteobacterial pathogen.
    DOI:  https://doi.org/10.1093/nar/gkae757
  38. Sci China Life Sci. 2024 Aug 29.
    Inhibition of the RXRA-PPARα-FABP4 signaling pathway alleviates vascular cellular aging by an SGLT2 inhibitor in an atherosclerotic mice model.
    Weiwei Zhang, Linghuan Wang, Yujia Wang, Yan Fang, Ruihua Cao, Zhiyi Fang, Dong Han, Xu Huang, Zhenghui Gu, Yingjie Zhang, Yan Zhu, Yan Ma, Feng Cao.
      Atherosclerosis is the pathological cause of atherosclerotic cardiovascular disease (ASCVD), which rapidly progresses during the cellular senescence. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) reduce major cardiovascular events in patients with ASCVD and have potential antisenescence effects. Here, we investigate the effects of the SGLT2 inhibitor dapagliflozin on cellular senescence in atherosclerotic mice. Compared with ApoE-/- control mice treated with normal saline, those in the ApoE-/- dapagliflozin group, receiving intragastric dapagliflozin (0.1 mg kg-1 d-1) for 14 weeks, exhibited the reduction in the total aortic plaque area (48.8%±6.6% vs. 74.6%±8.0%, P<0.05), the decrease in the lipid core area ((0.019±0.0037) mm2vs. (0.032±0.0062) mm2, P<0.05) and in the percentage of senescent cells within the plaques (16.4%±3.7% vs. 30.7%±2.0%, P<0.01), while the increase in the thickness of the fibrous cap ((21.6±2.1) µm vs. (14.6±1.5) µm, P<0.01). Transcriptome sequencing of the aortic arch in the mice revealed the involvement of the PPARα and the fatty acid metabolic signaling pathways in dapagliflozin's mechanism of ameliorating cellular aging and plaque progression. In vitro, dapagliflozin inhibited the expression of PPARα and its downstream signal FABP4, by which the accumulation of senescent cells in human aortic smooth muscle cells (HASMCs) was reduced under high-fat conditions. This effect was accompanied by a reduction in the intracellular lipid content and alleviation of oxidative stress. However, these beneficial effects of dapagliflozin could be reversed by the PPARα overexpression. Bioinformatics analysis and molecular docking simulations revealed that dapagliflozin might exert its effects by directly interacting with the RXRA protein, thereby influencing the expression of the PPARα signaling pathway. In conclusion, the cellular senescence of aortic smooth muscle cells is potentially altered by dapagliflozin through the suppression of the RXRA-PPARα-FABP4 signaling pathway, resulting in a deceleration of atherosclerotic progression.
    Keywords:  PPARα; SGLT2 inhibitors; atherosclerosis; cellular senescence
    DOI:  https://doi.org/10.1007/s11427-024-2602-7
  39. Cancer Discov. 2024 Sep 04. 14(9): 1581-1583
    Gene-Specific Machine Learning Models to Classify Driver Mutations in Clonal Hematopoiesis.
    Christopher M Arends, Siddhartha Jaiswal.
      There is no general consensus on the set of mutations capable of driving the age-related clonal expansions in hematopoietic stem cells known as clonal hematopoiesis, and current variant classifications typically rely on rules derived from expert knowledge. In this issue of Cancer Discovery, Damajo and colleagues trained and validated machine learning models without prior knowledge of clonal hematopoiesis driver mutations to classify somatic mutations in blood for 12 genes in a purely data-driven way. See related article by Demajo et al., p. 1717 (9).
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0751
  40. Crit Rev Food Sci Nutr. 2024 Aug 30. 1-27
    Nitrate: "the source makes the poison".
    E F Bowles, M Burleigh, A Mira, S G J Van Breda, E Weitzberg, B T Rosier.
      Interest in the role of dietary nitrate in human health and disease has grown exponentially in recent years. However, consensus is yet to be reached as to whether consuming nitrate from various food sources is beneficial or harmful to health. Global authorities continue to recommend an acceptable daily intake (ADI) of nitrate of 3.7 mg/kg-bw/day due to concerns over its carcinogenicity. This is despite evidence showing that nitrate consumption from vegetable sources, exceeding the ADI, is associated with decreased cancer prevalence and improvements in cardiovascular, oral, metabolic and neurocognitive health. This review examines the paradox between dietary nitrate and health and disease and highlights the key role of the dietary source and food matrix in moderating this interaction. We present mechanistic and epidemiological evidence to support the notion that consuming vegetable-derived nitrate promotes a beneficial increase in nitric oxide generation and limits toxic N-nitroso compound formation seen with high intakes of nitrate added during food processing or present in contaminated water. We demonstrate the need for a more pragmatic approach to nitrate-related nutritional research and guidelines. Ultimately, we provide an overview of our knowledge in this field to facilitate the various therapeutic applications of dietary nitrate, whilst maintaining population safety.
    Keywords:  Dietary nitrate; Health; Nitric oxide
    DOI:  https://doi.org/10.1080/10408398.2024.2395488
  41. Matrix Biol. 2024 Sep 01. pii: S0945-053X(24)00111-2. [Epub ahead of print]
    Hyaluronan and proteoglycan link protein 1 - a novel signaling molecule for rejuvenating aged skin.
    Zhicheng Fu, Goowon Yang, So Yoon Yun, Ji Min Jang, Hae Chan Ha, In Chul Shin, Moon Jung Back, Yongwei Piao, Dae Kyong Kim.
      The skin seems to rejuvenate upon exposure to factors within the circulation of young organisms. Intrinsic factors that modulate skin aging are poorly understood. We used heterochronic parabiosis and aptamer-based proteomics to identify serum-derived rejuvenating factors. We discovered a novel extracellular function of hyaluronan and proteoglycan link protein 1 (HAPLN1). Its serum levels decreased with age, disturbing the integrity of the skin extracellular matrix, which is predominantly composed of collagen I and hyaluronan; levels of various markers, which decrease in aged skin, were significantly restored in vivo and in vitro by the administration of recombinant human HAPLN1 (rhHAPLN1). rhHAPLN1 protected transforming growth factor beta receptor 2 on the cell surface from endocytic degradation via mechanisms such as regulation of viscoelasticity, CD44 clustering, and hyaluronan cross-linking. Moreover, rhHAPLN1 regulated the levels of nuclear factor erythroid 2-related factor 2, phosphorylated nuclear factor kappa B, and some cyclin-dependent kinase inhibitors such as p16 and p21. Therefore, rhHAPLN1 may act as a novel biomechanical signaling protein to rejuvenate aged skin.
    Keywords:  CD44; HAPLN1; TGF-β; collagen; hyaluronan; pericellular matrix
    DOI:  https://doi.org/10.1016/j.matbio.2024.08.009
  42. Curr Nutr Rep. 2024 Sep 06.
    Effects of Caloric Restriction and Intermittent Fasting and Their Combined Exercise on Cognitive Functioning: A Review.
    Junming Wang, Yifeng Rang, Chunhong Liu.
       PURPOSE OF REVIEW: The impact of dietary habits on cognitive function is increasingly gaining attention. The review is to discuss how caloric restriction (CR) and intermittent fasting (IF) can enhance cognitive function in healthy states through multiple pathways that interact with one another. Secondly, to explore the effects of CR and IF on cognitive function in conditions of neurodegenerative diseases, obesity diabetes and aging, as well as potential synergistic effects in combination with exercise to prevent cognitively related neurodegenerative diseases.
    RECENT FINDINGS: With age, the human brain ages and develops corresponding neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and epilepsy, which in turn trigger cognitive impairment. Recent research indicates that the impact of diet and exercise on cognitive function is increasingly gaining attention. The benefits of exercise for cognitive function and brain plasticity are numerous, and future research can examine the efficacy of particular dietary regimens during physical activity when combined with diet which can prevent cognitive decline.
    Keywords:  Caloric restriction; Cognitive; Exercise; Intermittent fasting; Neurodegenerative diseases
    DOI:  https://doi.org/10.1007/s13668-024-00570-8
  43. Nat Aging. 2024 Aug 29.
    ImAge quantitates aging and rejuvenation.
    Martin Alvarez-Kuglen, Kenta Ninomiya, Haodong Qin, Delany Rodriguez, Lorenzo Fiengo, Chen Farhy, Wei-Mien Hsu, Brian Kirk, Aaron Havas, Gen-Sheng Feng, Amanda J Roberts, Rozalyn M Anderson, Manuel Serrano, Peter D Adams, Tatyana O Sharpee, Alexey V Terskikh.
      For efficient, cost-effective and personalized healthcare, biomarkers that capture aspects of functional, biological aging, thus predicting disease risk and lifespan more accurately and reliably than chronological age, are essential. We developed an imaging-based chromatin and epigenetic age (ImAge) that captures intrinsic age-related trajectories of the spatial organization of chromatin and epigenetic marks in single nuclei, in mice. We show that such trajectories readily emerge as principal changes in each individual dataset without regression on chronological age, and that ImAge can be computed using several epigenetic marks and DNA labeling. We find that interventions known to affect biological aging induce corresponding effects on ImAge, including increased ImAge upon chemotherapy treatment and decreased ImAge upon caloric restriction and partial reprogramming by transient OSKM expression in liver and skeletal muscle. Further, ImAge readouts from chronologically identical mice inversely correlated with their locomotor activity, suggesting that ImAge may capture elements of biological and functional age. In sum, we developed ImAge, an imaging-based biomarker of aging with single-cell resolution rooted in the analysis of spatial organization of epigenetic marks.
    DOI:  https://doi.org/10.1038/s43587-024-00685-1
  44. BMB Rep. 2024 Sep 02. pii: 6212. [Epub ahead of print]
    Stromal cells and epigenetics: emerging key players of chronic inflammatory skin diseases.
    Jihye Kim, Michael Detmar.
      Epigenetic alterations play a crucial role in developmental processes, tissue regeneration, and cellular differentiation. Epigenetic changes are dynamically reversible. Various drugs that target DNA methyltransferases or histone deacetylases have demonstrated their ability to restore normal epigenetic patterns in a number of diseases. While the involvement of epigenetic modifications has been identified in chronic inflammatory diseases, their specific impact on skin inflammation in stromal cells remains unclear. This mini-review explores the role of stromal cells in chronic inflammatory skin diseases, focusing on epigenetic modifications of stromal cells such as fibroblasts, lymphatic, and blood vascular endothelial cells in both healthy and diseased skin. We also provide an overview of recent findings that highlight the contribution of stromal cells, including fibroblasts, to inflammatory and remodeling processes through epigenetic changes in the context of chronic inflammatory conditions. Investigating epigenetic reprogramming of stromal cells might lead to novel strategies for treating chronic inflammatory skin diseases.
  45. Life (Basel). 2024 Jul 31. pii: 962. [Epub ahead of print]14(8):
    Mitochondrial Adaptations in Aging Skeletal Muscle: Implications for Resistance Exercise Training to Treat Sarcopenia.
    Ilyoung Jeong, Eun-Jeong Cho, Jang-Soo Yook, Youngju Choi, Dong-Ho Park, Ju-Hee Kang, Seok-Hun Lee, Dae-Yun Seo, Su-Jeen Jung, Hyo-Bum Kwak.
      Sarcopenia, the age-related decline in muscle mass and function, poses a significant health challenge as the global population ages. Mitochondrial dysfunction is a key factor in sarcopenia, as evidenced by the role of mitochondrial reactive oxygen species (mtROS) in mitochondrial biogenesis and dynamics, as well as mitophagy. Resistance exercise training (RET) is a well-established intervention for sarcopenia; however, its effects on the mitochondria in aging skeletal muscles remain unclear. This review aims to elucidate the relationship between mitochondrial dynamics and sarcopenia, with a specific focus on the implications of RET. Although aerobic exercise training (AET) has traditionally been viewed as more effective for mitochondrial enhancement, emerging evidence suggests that RET may also confer beneficial effects. Here, we highlight the potential of RET to modulate mtROS, drive mitochondrial biogenesis, optimize mitochondrial dynamics, and promote mitophagy in aging skeletal muscles. Understanding this interplay offers insights for combating sarcopenia and preserving skeletal muscle health in aging individuals.
    Keywords:  aging; mitochondria; resistance exercise training; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.3390/life14080962
  46. China CDC Wkly. 2024 Aug 23. 6(34): 876-882
    PENG ZU Study on Healthy Aging in China (PENG ZU Cohort): Design and Goals.
    Ju Cui, Jing Pang, Liqun Zhang, Juan Li, Xiaolan Wu, Xinyi Zhu, Wei Ma, Senlin Luo, Huafang Gao, Zhao Wang, Jianping Cai, Tiemei Zhang.
      Life expectancy is increasing, leading to the continuous aging of the population in China. Enhancing the health status of the older population is crucial to achieving healthy aging. The primary objective of the PENG ZU Study on Healthy Aging in China (PENG ZU Cohort) is to understand the natural progression of health status among the aging Chinese population. Specifically, the PENG ZU cohort aims to identify and validate multidimensional aging markers, uncover the underlying mechanisms of systemic aging and functional decline, and develop novel strategies and measures to delay functional decline and adverse health outcomes, while maintaining overall good health. The PENG ZU cohort consists of 26,000 individuals aged 25 to 89 years from seven major geographical regions in China. Diversified data and biospecimens are collected according to standardized procedures at baseline and follow-up visits. Baseline recruitment for the PENG ZU cohort was completed in October 2021. The extensive analysis of multidimensional health-related data and bioresources collected from the cohort is anticipated to develop methods for evaluating functional status and elucidating multilevel, cross-scale interactions and regulatory mechanisms of healthy aging. The findings from this study will enhance the understanding of health changes due to aging, facilitate efficient and effective interventions to maintain functional ability, and reduce the incidence and severity of age-related diseases, thereby further promoting healthy aging.
    Keywords:  Functional Decline; Healthy Aging; PENG ZU Cohort
    DOI:  https://doi.org/10.46234/ccdcw2024.187
  47. Nat Commun. 2024 Sep 03. 15(1): 7653
    Yeast EndoG prevents genome instability by degrading extranuclear DNA species.
    Yang Yu, Xin Wang, Jordan Fox, Ruofan Yu, Pilendra Thakre, Brenna McCauley, Nicolas Nikoloutsos, Yang Yu, Qian Li, P J Hastings, Weiwei Dang, Kaifu Chen, Grzegorz Ira.
      In metazoans mitochondrial DNA (mtDNA) or retrotransposon cDNA released to cytoplasm are degraded by nucleases to prevent sterile inflammation. It remains unknown whether degradation of these DNA also prevents nuclear genome instability. We used an amplicon sequencing-based method in yeast enabling analysis of millions of DSB repair products. In non-dividing stationary phase cells, Pol4-mediated non-homologous end-joining increases, resulting in frequent insertions of 1-3 nucleotides, and insertions of mtDNA (NUMTs) or retrotransposon cDNA. Yeast EndoG (Nuc1) nuclease limits insertion of cDNA and transfer of very long mtDNA ( >10 kb) to the nucleus, where it forms unstable circles, while promoting the formation of short NUMTs (~45-200 bp). Nuc1 also regulates transfer of extranuclear DNA to nucleus in aging or meiosis. We propose that Nuc1 preserves genome stability by degrading retrotransposon cDNA and long mtDNA, while short NUMTs originate from incompletely degraded mtDNA. This work suggests that nucleases eliminating extranuclear DNA preserve genome stability.
    DOI:  https://doi.org/10.1038/s41467-024-52147-2
  48. Int J Biol Macromol. 2024 Sep 02. pii: S0141-8130(24)06062-8. [Epub ahead of print] 135256
    Structural characterization, anti-aging activity and mechanisms investigation in vivo of a polysaccharide from Anthriscus sylvestris.
    Xiaoyun Ji, Haimeng Luo, Xianyan Li, Siwei Wang, Lijun Xia, Maojun Ni, Jingxia Wang, Chaorong Peng, Xiaoqing Wu, Rui Tan, Xiaobin Zhang, Hezhong Jiang.
      Anthriscus sylvestris (L.) Hoffm has a long history of use for anti-aging, although the anti-aging properties of its decoction ingredients have been seldom explored. This study marks the first detailed examination of the in vivo anti-aging activity of A. sylvestris roots polysaccharide (AP). Structural analyses revealed that AP is a neutral heteropolysaccharide with an average molecular weight (Mw) of 34.17 kDa, comprising glucose, xylose, galactose, mannose, and arabinose, with a backbone primarily of 1,4-α-D-Glc and minor branching at 1,4,6-α-D-Man. Its advanced structure is characterized by stable triple-helical chains and nanoscale agglomerated spherical particles. Using a D-gal-induced aging mouse model, further investigation showed that AP boosts the activity of various antioxidant enzymes via the Nrf2/HO-1/NQO1 signaling pathway. Aging-related immune decline was also mitigated by an increase in lymphocyte production in thymus. Moreover, AP reduced inflammation and downregulated aging genes p53 and p21 in hippocampus and liver tissues, enhanced the cholinergic system, and improved liver functions and lipid metabolism. The collective impact of these mechanisms underscores the robust anti-aging properties of AP. These findings highlight the anti-aging and immunomodulatory potential of A. sylvestris polysaccharide, broadening the understanding of its active components.
    Keywords:  Anthriscus sylvestris polysaccharide; Anti-aging activity; Anti-oxidative stress; D-gal aging mice; Immunomodulation
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.135256
  49. Clin Cosmet Investig Dermatol. 2024 ;17 1943-1962
    Regulatory Mechanisms of Natural Active Ingredients and Compounds on Keratinocytes and Fibroblasts in Mitigating Skin Photoaging.
    Xinru Hu, Meng Chen, Jahanzeb Nawaz, Xi Duan.
       Background: The mechanism underlying skin photoaging remains elusive because of the intricate cellular and molecular changes that contribute to this phenomenon, which have yet to be elucidated. In photoaging, the roles of keratinocytes and fibroblasts are vital for maintaining skin structure and elasticity. But these cells can get photo-induced damage during photoaging, causing skin morphological changes. Recently, the function of natural active ingredients in treating and preventing photoaging has drawn more attention, with researches often focusing on keratinocytes and fibroblasts.
    Methods: We searched for studies published from 2007 to January 2024 in the Web of Science, PubMed, and ScienceDirect databases through the following keywords: natural plant, natural plant products or phytochemicals, traditional Chinese Medicine or Chinese herbal, plant extracts, solar skin aging, skin photoaging, and skin wrinkling. This review conducted the accordance of Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines.
    Results: In total, 87 researches were included in this review (Figure 1). In keratinocytes, natural compounds may primarily regulate signal pathways such as the NF-κB, MAPK, PI3K/AKT, and Nrf2/ARE pathways, reducing inflammation and cellular damage, thus slowing skin photoaging. Additionally, in fibroblasts, natural active ingredients primarily promote the TGF-β pathway, inhibit MMPs activity, and enhance collagen synthesis while potentially modulating the mTOR pathway, thereby protecting the dermal collagen network and reducing wrinkle formation. Several trials showed that natural compounds that regulate keratinocytes and fibroblasts responses have significant and safe therapeutic effects.
    Conclusion: The demand for natural product-based ingredients in sunscreen formulations is rising. Natural compounds show promising anti-photoaging effects by targeting cellular pathways in keratinocytes and fibroblasts, providing potential therapeutic strategies. However, comprehensive clinical studies are needed to verify their efficacy and safety in mitigating photoaging, which should use advanced pharmacological methods to uncover the complex anti-photoaging mechanisms of natural compounds.
    Keywords:  fibroblasts; keratinocytes; natural compounds; natural ingredients; photoaging
    DOI:  https://doi.org/10.2147/CCID.S478666
  50. Adv Sci (Weinh). 2024 Sep 03. e2404622
    Recognition and Sequencing of Mutagenic DNA Adduct at Single-Base Resolution Through Unnatural Base Pair.
    Honglei Wang, Wenchao Tie, Wuyuan Zhu, Shuyuan Wang, Ruzhen Zhang, Jianlin Duan, Bingyu Ye, Anlian Zhu, Lingjun Li.
      DNA lesions are linked to cancer, aging, and various diseases. The recognition and sequencing of special DNA lesions are of great interest but highly challenging. In this paper, an unnatural-base-pair-promoting method for sequencing highly mutagenic ethenodeoxycytidine (εC) DNA lesions that occurred frequently is developed. First, a promising unnatural base pair of dεC-dNaM to recognize εC lesions is identified, and then a conversion PCR is developed to site-precise transfer dεC-dNaM to dTPT3-dNaM for convenient Sanger sequencing. The low sequence dependence of this method and its capacity for the enrichment of dεC in the abundance of as low as 1.6 × 10-6 nucleotides is also validated. Importantly, the current method can be smoothly applied for recognition, amplification, enrichment, and sequencing of the real biological samples in which εC lesions are generated in vitro or in vivo, thus offering the first sequencing methodology of εC lesions at single-base resolution. Owing to its simple operations and no destruction of inherent structures of DNA, the unnatural-base-pair strategy may provide a new platform to produce general tools for the sequencing of DNA lesions that are hardly sequenced by traditional strategies.
    Keywords:  3,4‐ethenodeoxycytidine; DNA etheno lesions; sequencing; unnatural base pairs
    DOI:  https://doi.org/10.1002/advs.202404622
  51. Life Sci. 2024 Aug 28. pii: S0024-3205(24)00609-X. [Epub ahead of print]356 123019
    Engineered exosome therapeutics for neurodegenerative diseases.
    Biplob Saikia, Anandh Dhanushkodi.
      An increase in life expectancy comes with a higher risk for age-related neurological and cognitive dysfunctions. Given the psycho-socioeconomic burden due to unhealthy aging in the coming decades, the United Nations has declared 2021-2030 as a decade of healthy aging. In this line, multipotent mesenchymal stromal cell-based therapeutics received special interest from the research community. Based on decades of research on cell therapy, a consensus has emerged that the therapeutic effects of cell therapy are due to the paracrine mechanisms rather than cell replacement. Exosomes, a constituent of the secretome, are nano-sized vesicles that have been a focus of intense research in recent years as a possible therapeutic agent or as a cargo to deliver drugs of interest into the central nervous system to induce neurogenesis, reduce neuroinflammation, confer neuroregeneration/neuroprotection, and improve cognitive and motor functions. In this review, we have discussed the neuroprotective properties of exosomes derived from adult mesenchymal stem cells, with a special focus on the role of exosomal miRNAs. We also reviewed various strategies to improve exosome production and their content for better therapeutic effects. Further, we discussed the utilization of ectomesenchymal stem cells like dental pulp stem cells and their exosomes in treating neurodegenerative diseases.
    Keywords:  Ectomesenchymal stem cells; Exosomal miRNA; Exosome engineering; Exosome therapeutics; Neurodegeneration; Neuroprotection
    DOI:  https://doi.org/10.1016/j.lfs.2024.123019
  52. bioRxiv. 2024 Aug 22. pii: 2024.05.17.594714. [Epub ahead of print]
    The CALERIE™ Genomic Data Resource.
    Calen Patrick Ryan, David L Corcoran, Nirad Banskota, Claire Eckstein Indik, Aristidis Floratos, Richard A Friedman, Michael S Kobor, Virginia Byers Kraus, William Kraus, Julie L MacIsaac, Melissa C Orenduff, Carl F Pieper, James P White, Luigi Ferrucci, Steve Horvath, Kim M Huffman, Daniel W Belsky.
      Caloric restriction (CR) slows biological aging and prolongs healthy lifespan in model organisms. Findings from CALERIE-2™ - the first ever randomized, controlled trial of long-term CR in healthy, non-obese humans - broadly supports a similar pattern of effects in humans. To expand our understanding of the molecular pathways and biological processes underpinning CR effects in humans, we generated a series of genomic datasets from stored biospecimens collected from n=218 participants during the trial. These data constitute the first publicly-accessible genomic data resource for a randomized controlled trial of an intervention targeting the biology of aging. Datasets include whole-genome SNP genotypes, and three-timepoint-longitudinal DNA methylation, mRNA, and small RNA datasets generated from blood, skeletal muscle, and adipose tissue samples (total sample n=2327). The CALERIE Genomic Data Resource described in this article is available from the Aging Research Biobank. This multi-tissue, multi-omic, longitudinal data resource has great potential to advance translational geroscience.
    DOI:  https://doi.org/10.1101/2024.05.17.594714
  53. Autophagy. 2024 Sep 03. 1-14
    ABHD8 antagonizes inflammation by facilitating chaperone-mediated autophagy-mediated degradation of NLRP3.
    Shuai Yang, Mengqiu Li, Guangyu Lian, Yaoxing Wu, Jun Cui, Liqiu Wang.
      The NLRP3 inflammasome is a multiprotein complex that plays a vital role in the innate immune system in response to microbial infections and endogenous danger signals. Aberrant activation of the NLRP3 inflammasome is implicated in a spectrum of inflammatory and autoimmune diseases, emphasizing the necessity for precise regulation of the NLRP3 inflammasome to maintain immune homeostasis. The protein level of NLRP3 is a limiting step for inflammasome activation, which must be tightly controlled to avoid detrimental consequences. Here, we demonstrate that ABHD8, a member of the α/β-hydrolase domain-containing (ABHD) family, interacts with NLRP3 and promotes its degradation through the chaperone-mediated autophagy (CMA) pathway. ABHD8 acts as a scaffold to recruit palmitoyltransferase ZDHHC12 to NLRP3 for its palmitoylation as well as subsequent CMA-mediated degradation. Notably, ABHD8 deficiency results in the stabilization of NLRP3 protein and promotes NLRP3 inflammasome activation. We further confirm that ABHD8 overexpression ameliorates LPS- or alum-triggered NLRP3 inflammasome activation in vivo. Interestingly, the nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impairs the ABHD8-NLRP3 association, resulting in an elevation in NLRP3 protein level and excessive inflammasome activation. These findings demonstrate that ABHD8 May represent a potential therapeutic target in conditions associated with NLRP3 inflammasome dysregulation.Abbreviations: 3-MA: 3-methyladenine; ABHD: α/β-hydrolase domain-containing; BMDMs: Bone marrow-derived macrophages; CFZ: carfilzomib; CHX: cycloheximide; CMA: chaperone-mediated autophagy; CQ: chloroquine; DAMPs: danger/damage-associated molecular patterns; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; LAMP2A: lysosomal associated membrane protein 2A; NH4Cl: ammonium chloride; NLRP3: NLR family pyrin domain containing 3; PAMPs: pathogen-associated molecular patterns; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.
    Keywords:  ABHD8; CMA; NLRP3; inflammasome; palmitoylation
    DOI:  https://doi.org/10.1080/15548627.2024.2395158
  54. Biomed Mater Eng. 2024 Aug 29.
    Mesenchymal stem cells derived from human adipose tissue exhibit significantly higher chondrogenic differentiation potential compared to those from rats.
    Faisal Yaqoob, Muhammad Khizer Hayat, Muhammad Sharjeel Chaughtai, Sehrish Khan, Musa Bin Bashir.
       BACKGROUND: Osteoarthritis is a prevalent joint disease affecting both humans and animals. It is characterized by articular cartilage degeneration and joint surface eburnation. Currently, no effective pharmacological treatment is available to restore the original function and structure of defective cartilage.
    OBJECTIVE: This study explores the potential of stem cell-based therapy in treating joint diseases involving cartilage degeneration, offering a promising avenue for future research and treatment. The primary aim was to compare the characteristics and, more importantly, the chondrogenic differentiation potential of human and rat adipose-derived mesenchymal stem cells (AD-MSCs).
    METHODS: Rat adipose tissue was collected from Sprague Dawley rats, while human adipose tissue was obtained in the form of lipoaspirate. The mesenchymal stem cells (MSCs) were then harvested using collagenase enzyme and subcultured. We meticulously evaluated and compared the cell morphology, percentage of cell viability, population doubling time, metabolic proliferation, and chondrogenic differentiation potential of MSCs harvested from both sources. Chondrogenic differentiation was induced at passage 3 using the 3D pellet culture method and assessed through histological and molecular analysis.
    RESULTS: The findings revealed that human and rat AD-MSCs were phenotypically identical, and an insignificant difference was found in cell morphology, percentage of cell viability, metabolic proliferation, and population doubling time. However, the chondrogenic differentiation potential of human AD-MSCs was evaluated as significantly higher than that of rat AD-MSCs.
    CONCLUSION: The current study suggests that research regarding chondrogenic differentiation of rat AD-MSCs can be effectively translated to humans. This discovery is a significant contribution to the field of regenerative medicine and has the potential to advance our understanding of stem cell-based therapy for joint diseases.
    Keywords:  Adipose tissue; chondrogenic differentiation; lipoaspirate; mesenchymal stem cell; osteoarthritis
    DOI:  https://doi.org/10.3233/BME-240062
  55. Nature. 2024 Aug 30.
    Researchers built an 'AI Scientist' - what can it do?
    Davide Castelvecchi.
      
    Keywords:  Machine learning
    DOI:  https://doi.org/10.1038/d41586-024-02842-3
  56. bioRxiv. 2024 Jul 31. pii: 2024.07.31.606047. [Epub ahead of print]
    DNA stimulates SIRT6 to mono-ADP-ribosylate proteins within histidine repeats.
    Nicholas J Pederson, Katharine L Diehl.
      Sirtuins are the NAD + -dependent class III lysine deacylases (KDACs). Members of this family have been linked to longevity and a wide array of different diseases, motivating the pursuit of sirtuin modulator compounds. Sirtuin 6 (SIRT6) is a primarily nuclear KDAC that deacetylates histones to facilitate gene repression. In addition to this canonical post-translational modification (PTM) "eraser" function, SIRT6 can use NAD + instead to "write" mono-ADP-ribosylation (mARylation) on target proteins. This enzymatic function has been primarily associated with SIRT6's role in the DNA damage response. This modification has been challenging to study because it is not clear under what precise cellular contexts it occurs, only a few substrates are known, and potential interference from other ADP-ribosyltransferases in cells, among other reasons. In this work, we used commercially available ADP-ribosylation detection reagents to investigate the mARylation activity of SIRT6 in a reconstituted system. We observed that SIRT6 is activated in its mARylation activity by binding to dsDNA ends. We further identified a surprising target motif within biochemical substrates of SIRT6, polyhistidine (polyHis) repeat tracts, that are present in several previously identified SIRT6 mARylation substrates and binding partners. This work provides important context for SIRT6 mARylation activity, in contrast to its KDAC activity, and proposes that SIRT6 is a histidine mARyltransferase enzyme.
    DOI:  https://doi.org/10.1101/2024.07.31.606047
  57. Adv Sci (Weinh). 2024 Sep 04. e2406668
    A Single-Cell Metabolic Profiling Characterizes Human Aging via SlipChip-SERS.
    Fugang Liu, Jiaqing Liu, Yang Luo, Siyi Wu, Xu Liu, Haoran Chen, Zhewen Luo, Haitao Yuan, Feng Shen, Fangfang Zhu, Jian Ye.
      Metabolic dysregulation is a key driver of cellular senescence, contributing to the progression of systemic aging. The heterogeneity of senescent cells and their metabolic shifts are complex and unexplored. A microfluidic SlipChip integrated with surface-enhanced Raman spectroscopy (SERS), termed SlipChip-SERS, is developed for single-cell metabolism analysis. This SlipChip-SERS enables compartmentalization of single cells, parallel delivery of saponin and nanoparticles to release intracellular metabolites and to realize SERS detection with simple slipping operations. Analysis of different cancer cell lines using SlipChip-SERS demonstrated its capability for sensitive and multiplexed metabolic profiling of individual cells. When applied to human primary fibroblasts of different ages, it identified 12 differential metabolites, with spermine validated as a potent inducer of cellular senescence. Prolonged exposure to spermine can induce a classic senescence phenotype, such as increased senescence-associated β-glactosidase activity, elevated expression of senescence-related genes and reduced LMNB1 levels. Additionally, the senescence-inducing capacity of spermine in HUVECs and WRL-68 cells is confirmed, and exogenous spermine treatment increased the accumulation and release of H2O2. Overall, a novel SlipChip-SERS system is developed for single-cell metabolic analysis, revealing spermine as a potential inducer of senescence across multiple cell types, which may offer new strategies for addressing ageing and ageing-related diseases.
    Keywords:  SlipChip; aging; metabolic profiling; single‐cell; surface‐enhanced Raman spectroscopy
    DOI:  https://doi.org/10.1002/advs.202406668
  58. Postgrad Med J. 2024 Sep 06. pii: qgae115. [Epub ahead of print]
    Causal linkage of psoriasis with ageing: Mendelian randomization and enrichment analysis towards telomere length and psoriasis.
    Ziqin Cao, Yajia Li, Jianhuang Wu.
       OBJECTIVE: Several studies demonstrated potential associations between the telomere length (TL) in leukocytes and psoriasis or psoriatic arthritis (PsA). This study aimed to investigate whether there was the causal genetic relationship between TL and psoriatic diseases bidirectionally.
    METHODS: Two-sample univariable MR (UVMR) analysis was applied to explore the bidirectional causal association of TL with overall psoriasis, psoriasis vulgaris (PV) and PsA. Multivariable MR (MVMR) and the mediation effects analysis were applied to test whether the bidirectional associations between TLs and psoriasis were mediated by body mass index (BMI), alcohol, and smoking status.
    RESULTS: According to the UVMR results, a negative causal impact of TL on the risk of overall psoriasis was found (OR = 0.775; 95% CI: 0.646-0.931; P = 6.36 × 10-3), and a similar trend was observed in the reversed direction for psoriasis-TL (IVW-β = -0.0097; 95% CI: -0.0170 to -0.0024; P = 9.12 × 10-3). There were also negative genetic associations between TL and PV bidirectionally. The independent association of genetically predicted TL and overall psoriasis persisted in the MVMR results controlled for BMI, smoking, and alcohol consumption (ORMVMR = 0.736; 95% CI: 0.597 to 0.907; P = 0.004). An independent significant association of genetic predisposition to PsA with TL was also found (βMVMR = 0.006; 95% CI: 0.001 to 0.012; P = 0.033). The mediation analysis showed that BMI partially mediated the reverse association between PSO and TL.
    CONCLUSION: This MR study revealed an association between genetic indicators of shortened TL and risk of overall psoriasis and PV, and genetic predisposition to PsA was associated with longer TL. Key message What is already known on this topic?  Telomere length (TL) is acknowledged to reflect an individual's biological age but is also associated with dysregulated immune function and immunosenescence. The impact of aging on psoriasis is controversial. Existing evidence suggests that aging may influence pathological changes and clinical course but whether aging is an independent risk factor remains unclear. What this study adds?  The current study found an association between genetic indicators of shortened TL and the risk of overall psoriasis and psoriasis vulgaris (PV). There was a bidirectional link between genetically indicated overall psoriasis and shortened TL. A possible positive genetic association between PsA and TL was also found. How this study might affect research, practice, or policy?  Our study may provide evidence for TL as new diagnostic and therapeutic strategies in clinical practices for psoriasis. Greater efforts to psoriasis management may substantially reduce the aging attributable to TL shortening. Future large-scale GWAS and experimental studies are warranted to examine the mechanistic basis for links between TL and psoriasis to improve understanding and illuminate possible therapeutic targets for psoriatic disease.
    Keywords:  Mendelian randomization; psoriasis; psoriatic arthritis; telomere length
    DOI:  https://doi.org/10.1093/postmj/qgae115
  59. Iran J Biotechnol. 2024 Apr;22(2): e3863
    DNA Methyltransferase Inhibition by RG108 Improves Stemness and Multipotential Differentiation of Human Adipose Tissue-derived Stem Cells.
    Razieh Asgharian, Afrooz Hashemi, Arash Javeri, Masoumeh Fakhr Taha.
       Background: DNA methylation plays important roles in regulating various biological processes, including self-renewal, differentiation and regenerative capacity of stem cells. Previous studies have demonstrated that lineage-specific differentiation of mesenchymal stem cells can be promoted using nontoxic chromatin-modifying drugs.
    Objectives: Here we evaluated the impact of RG108, a known DNA methyltransferase inhibitor, on the expression of pluripotency genes in human adipose tissue-derived stem cells (hADSCs) and their proliferation and differentiation.
    Materials and Methods: Human ADSCs were isolated by collagenase treatment and characterized. Then, ADSCs were treated with 5 µM RG108 for four days. The control and RG108-treated cells were analyzed for the cell cycle progression, apoptosis and the expression of pluripotency genes. Also, ADSCs were cultured in adipogenic and osteogenic differentiation media for three weeks and were assessed by Oil Red O and Alizarin Red S staining and qPCR analysis.
    Results: We showed that RG108 treatment increased proliferation of hADSCs and upregulated the expression of pluripotency-related genes. Additionally, RG108 had a positive impact on the differentiation capability of ADSCs. This was evident through elevated levels of Oil Red O staining in the RG108 treatment group. Also, qPCR analysis showed the upregulation of some adipogenic and osteogenic markers by RG108.
    Conclusion: These findings indicate that pretreatment with RG108 improves the differentiation potential of ADSCs, probably making these cells more beneficial for cell therapy applications.
    Keywords:   Adipocyte; Adipose tissue-derived stem Cells (ADSCs); Differentiation; Osteocyte; Pluripotency; RG108
    DOI:  https://doi.org/10.30498/ijb.2024.435096.3863
  60. Trends Endocrinol Metab. 2024 Sep 02. pii: S1043-2760(24)00223-6. [Epub ahead of print]
    A new clinical age of aging research.
    Zhen Zhang, Renlei Yang, Zhike Zi, Baohua Liu.
      Aging is a major risk factor for a variety of diseases, thus, translation of aging research into practical applications is driven by the unmet need for existing clinical therapeutic options. Basic and translational research efforts are converging at a critical stage, yielding insights into how fundamental aging mechanisms are used to identify promising geroprotectors or therapeutics. This review highlights several research areas from a clinical perspective, including senescent cell targeting, alleviation of inflammaging, and optimization of metabolism with endogenous metabolites or precursors. Refining our understanding of these key areas, especially from the clinical angle, may help us to better understand and attenuate aging processes and improve overall health outcomes.
    Keywords:  endogenous metabolites; inflammaging; senolytics
    DOI:  https://doi.org/10.1016/j.tem.2024.08.004
  61. Nutrients. 2024 Aug 22. pii: 2810. [Epub ahead of print]16(16):
    Macrofungal Extracts as a Source of Bioactive Compounds for Cosmetical Anti-Aging Therapy: A Comprehensive Review.
    Maja Paterska, Bogusław Czerny, Judyta Cielecka-Piontek.
      For centuries, mushrooms have been used as a component of skincare formulations. Environmental stresses and a modern lifestyle expose the skin to accelerated aging. To slow down this process, natural anti-aging skincare ingredients are being sought. In this review, 52 scientific publications about the effects of chemical compounds extracted from the fruiting bodies of macrofungi on skin cells were selected. The effects of extracts from nine species that are tested for anti-aging effects have been described. According to available literature data, macrofungi contain many polysaccharides, phenolic compounds, polysaccharide peptides, free amino acids, sterols, proteins, glycosides, triterpenes, alkaloids, which can have an anti-aging effect on the skin by acting as antioxidants, photoprotective, skin whitening, moisturizing, anti-inflammatory and stabilizing collagen, elastin and hyaluronic acid levels in the skin.
    Keywords:  Agaricus subrufescens; Ganoderma lucidum; Inonotus obliquus; Letinula edodes; Pleurotus ostreatus; Schizophyllum commune; Trametes versicolor; Tremella fuciformis; Volvariella volvacea; anti-aging; macrofungi; mushrooms
    DOI:  https://doi.org/10.3390/nu16162810
  62. Comb Chem High Throughput Screen. 2024 Sep 03.
    Zuogui Pills Improve the Learning and Memory Ability of Brain-Aging Mice through the Estrogen Receptor ERα Methylation Pathway.
    Yang Huang, Lili Zhong, Jing Yang, Qiaomei Dai, Li Zhao, Mengdi Zhang, Hong Liu.
       INTRODUCTION: Sex hormones are important factors in maintaining brain function and acting as brain protectors. Recent research suggests that neuronal damage in brain aging may be linked to the methylation of the estrogen receptor α (ERα). However, the mechanism of Zuogui Pills (ZGW) in brain-aging ERα DNA methylation and neuronal repair remains unknown.
    MATERIALS AND METHODS: D-galactose-induced ovary removal mice were used as a model of aging. Changes in estrous cycle were detected in mice by vaginal cell smear. Animal behavior tests, including the Morris water maze (MWM) and new object recognition (NOR) test, were conducted. Hematoxylin-eosin (HE) and Nissl-staining were carried out to assess hippocampal neurogenesis. Enzyme-linked immunosorbent assay (ELISA) was performed for 5- methylcytosine methylation levels, and immunohistochemistry (IHC) and western blotting (WB) experiments were performed to assess ERα/DNA methyltransferase 1 (DNMT1) expression after ZGW treatment. Finally, bisulfite sequencing PCR (BSP) analysis was performed to identify methylated differentially expressed estrogen receptor 1 (ESR1) gene in D-gal-induced senescent neurons before and after ZGW treatment.
    RESULTS: We found that ERα methylation was involved in the delayed brain ageing process of ZGW. Mechanistically, ZGW can improve the learning and memory ability of brain-aging mice, reduce the expression of 5-methylcytosine (5-mc) in serum, increase the amount of ERα, inhibit the expression of DNMT1, and significantly reduce methylated expression of the ESRI gene.
    CONCLUSION: Our data suggested that ZGW slowed down D-gal-induced brain aging in mice, and these results showed that ZGW is beneficial for aging. It may be used for neuronal protection in aging.
    Keywords:  DNA methylation.; ERα; Memory; Zuogui pill; anti-aging
    DOI:  https://doi.org/10.2174/0113862073306093240820113714
  63. bioRxiv. 2024 Aug 09. pii: 2024.08.08.607218. [Epub ahead of print]
    Ophthalmic acid is a bloodborne metabolite that contributes to age-induced cardiomyocyte hypertrophy.
    Melod Mehdipour, Sangsoon Park, Wei Wei, Jonathan Z Long, Guo N Huang.
      Cardiac aging involves the development of left ventricular hypertrophy alongside a decline in functional capacity. Here, we use neutral blood exchange to demonstrate that the acute removal of age-accumulated blood factors significantly regresses cardiac hypertrophy in aged mice. The reversal of hypertrophy was not attributed to age-associated hemodynamic effects, implicating a role of blood-derived factors. In addition, the overarching paradigm of systemic aging maintains that the age-related overabundance of plasma proteins are largely responsible for causing pathological phenotypes in tissues. Our results suggest that blood metabolites, not proteins, drive cardiac hypertrophy instead. Upon analyzing serum metabolomics data sets, we identified ophthalmic acid as a circulating metabolite whose levels increase with advanced age. Treatment of adult mouse and neonatal rat cardiomyocytes in culture with ophthalmic acid increased their relative surface areas. This study uncovers a non-protein metabolite that may contribute to cardiomyocyte hypertrophy during aging. Identifying a method to counteract ophthalmic acid's hypertrophic effects may reveal novel therapeutic opportunities for cardiac rejuvenation.
    DOI:  https://doi.org/10.1101/2024.08.08.607218
  64. Med Res Rev. 2024 Aug 31.
    Activation and inhibition of sirtuins: From bench to bedside.
    Francesco Fiorentino, Emanuele Fabbrizi, Antonello Mai, Dante Rotili.
      The sirtuin family comprises seven NAD+-dependent enzymes which catalyze protein lysine deacylation and mono ADP-ribosylation. Sirtuins act as central regulators of genomic stability and gene expression and control key processes, including energetic metabolism, cell cycle, differentiation, apoptosis, and aging. As a result, all sirtuins play critical roles in cellular homeostasis and organism wellness, and their dysregulation has been linked to metabolic, cardiovascular, and neurological diseases. Furthermore, sirtuins have shown dichotomous roles in cancer, acting as context-dependent tumor suppressors or promoters. Given their central role in different cellular processes, sirtuins have attracted increasing research interest aimed at developing both activators and inhibitors. Indeed, sirtuin modulation may have therapeutic effects in many age-related diseases, including diabetes, cardiovascular and neurodegenerative disorders, and cancer. Moreover, isoform selective modulators may increase our knowledge of sirtuin biology and aid to develop better therapies. Through this review, we provide critical insights into sirtuin pharmacology and illustrate their enzymatic activities and biological functions. Furthermore, we outline the most relevant sirtuin modulators in terms of their modes of action, structure-activity relationships, pharmacological effects, and clinical applications.
    Keywords:  cancer; drug discovery; metabolism; protein lysine deacylation; sirtuins
    DOI:  https://doi.org/10.1002/med.22076
  65. Nat Protoc. 2024 Aug 30.
    A bioswitchable delivery system for microRNA therapeutics based on a tetrahedral DNA nanostructure.
    Songhang Li, Taoran Tian, Tao Zhang, Yunfeng Lin, Xiaoxiao Cai.
      As microRNAs (miRNA) regulate almost all physiopathological activities in the human body, miRNA therapeutics that deliver miRNA regulators have attracted considerable attention in the field of nucleic acid drug development. The use of tetrahedral DNA nanostructures to deliver miRNA regulators is promising because of their simple fabrication, enhanced cell entry, effective tissue penetration, biocompatibility and functional editability. This protocol extension builds on our previous protocol for the use of tetrahedral DNA nanostructures and was designed to establish an updated bioswitchable delivery system (BDS) for achieving controlled cargo loading and release. A ribonuclease H-sensitive sequence is designed as a bioswitchable apparatus for the targeted release of the miRNA regulator. The functional sequence of the miRNA regulator and minimal secondary structure formation tendency during annealing are two key points in cargo design. We provide two BDS design strategies; BDS-A comprises an intact DNA tetrahedron with the RNA cargo hanging outside, offering the merits of lower cost, simplicity, and more direct structural design. In the BDS-B design, the RNA regulators are embedded into the DNA tetrahedron, which is beneficial for dermal tissue permeation applications. Following sequence design in Oligo 7 and Tiamat, the BDS assembly is completed and then ribonuclease H achieves controlled release of the miRNA regulator by triggering the bioswitchable apparatus. This is verified via polyacrylamide and agarose gel electrophoresis or fluorophore modifications. Both BDSs show promising cellular membrane permeability, tissue permeability and target inhibition in vitro and in vivo. The assembly and characterization of the BDS can be completed in 4 d, and the validation time for biostability and biological applications will depend on the specific use.
    DOI:  https://doi.org/10.1038/s41596-024-01050-7
  66. Regen Biomater. 2024 ;11 rbae100
    Calcium silicate cements endowing bioactivity and sustaining mechanical strength of low-heat-releasing and fast-curing magnesium phosphate cements.
    Lijun Xie, Yan Zhang, Binji Cao, Xiaoyi Jiao, Xusong Yue, Yan Xu, Xianyan Yang, Guojing Yang, Yingjie Wang, Jian Shen, Cong Wang, Xisheng Weng, Zhongru Gou.
      It is known that magnesium phosphate cements (MPCs) show appreciable mechanical strength and biocompatibility, but the hydration reaction processes often lead to intense heat release while the hydration products present weak resistance to mechanical decay and low bioactivity. Herein we developed an MPC-based system, which was low-heat-releasing and fast-curing in this study, by compounding with self-curing calcium silicate cements (CSCs). The MPC composed of magnesium oxide (MgO), potassium dihydrogen phosphate (KH2PO4), disodium hydrogen phosphate (Na2HPO4), magnesium hydrogen phosphate trihydrate (MgHPO4·3H2O) and chitosan were weakly basic, which would be more stable in vivo. The physicochemical properties indicated that the addition of CSCs could increase the final setting time while decrease the heat release. Meanwhile, the CSCs could endow MPC substrate with apatite re-mineralization reactivity, especially, which add 25 wt.% CSCs showed the most significant apatite deposition. What's more, the mechanical evolution in buffer demonstrated CSCs could enhance and sustain the mechanical strength during degradation, and the internal constructs of cement implants could still be reconstructed by μCT analysis in rabbit femoral bone defect model in vivo. Particularly, appropriate CSCs adjusted the biodegradation and promoted new bone tissue regeneration in vivo. Totally, the MPC/CSCs composite system endows bioactivity and sustains mechanical strength of the MPC, which may be promising for expending the clinical applications of MPC-based bone cements.
    Keywords:  bioactivity; bone tissue regeneration; calcium silicate cements; magnesium phosphate cements; mechanical property
    DOI:  https://doi.org/10.1093/rb/rbae100
  67. bioRxiv. 2024 Aug 19. pii: 2024.08.17.608411. [Epub ahead of print]
    Macrophage WDFY3, a protector against autoimmunity.
    Xun Wu, Ziyi Wang, Katherine R Croce, Fang Li, Jian Cui, Vivette D D'Agati, Rajesh K Soni, Shareef Khalid, Danish Saleheen, Ira Tabas, Ai Yamamoto, Hanrui Zhang.
      Efficient efferocytosis is essential for maintaining homeostasis. Excessive apoptotic cell (AC) death and impaired macrophage efferocytosis lead to autoantigen release and autoantibody production, immune activation, and organ damage. It remains unclear whether these immunogenic autoantigens are the sole cause of increased autoimmunity or if efferocytosis of ACs directly influences macrophage function, impacting their ability to activate T cells and potentially amplifying autoimmune responses. Additionally, it has not been established if enhancing macrophage efferocytosis or modulating macrophage responses to AC engulfment can be protective in autoimmune-like disorders. Our previous work showed WDFY3 is crucial for efficient macrophage efferocytosis. This study reveals that myeloid knockout of Wdfy3 exacerbates autoimmunity in young mice with increased AC burden by systemic injections of ACs and in middle-aged mice developing spontaneous autoimmunity, whereas ectopic overexpression of WDFY3 suppresses autoimmunity in these models. Macrophages, as efferocytes, can activate T cells and the inflammasome upon engulfing ACs, which are suppressed by overexpressing WDFY3. This work uncovered the role of WDFY3 as a protector against autoimmunity by promoting macrophage efferocytosis thus limiting autoantigen production, as well as mitigating T cell activation and inflammasome activation.
    DOI:  https://doi.org/10.1101/2024.08.17.608411
  68. Angew Chem Int Ed Engl. 2024 Sep 04. e202411203
    Cell-Permeable Nicotinamide Adenine Dinucleotides for Exploration of Cellular Protein ADP-Ribosylation.
    Renata Kasprzyk, Sonja Rieth, Peter Heid, Florian Stengel, Andreas Marx.
      Posttranslational modifications (PTMs) greatly enhance the functional diversity of proteins, surpassing the number of gene-encoded variations. One intriguing PTM is ADP-ribosylation, which utilizes nicotinamide adenine dinucleotide (NAD+) as a substrate and is essential in cell signaling pathways regulating cellular responses. Here, we report the first cell-permeable NAD+ analogs and demonstrate their utility for investigating cellular ADP-ribosylation. Using a desthiobiotin-labelled analog for affinity enrichment of proteins that are ADP-ribosylated in living cells under oxidative stress, we identified protein targets associated with host-virus interactions, DNA damage and repair, protein biosynthesis, and ribosome biogenesis. Most of these targets have been noted in various literature sources, highlighting the potential of our probes for cellular ADP-ribosylome studies.
    Keywords:  NAD+; Nucleotide synthesis; Nucleotides; Post-translational modifications; chemical biology
    DOI:  https://doi.org/10.1002/anie.202411203
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