bims-caglex Biomed News
on Cellular aging and life extension
Issue of 2024‒05‒12
twenty-one papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño
  1. Targeting senescent cells with NKG2D-CAR T cells.
  2. Caloric restriction mitigates age-associated senescence characteristics in subcutaneous adipose tissue-derived stem cells.
  3. From cup to clock: exploring coffee's role in slowing down biological aging.
  4. Nature of epigenetic aging from a single-cell perspective.
  5. Cellular senescence, DNA damage, and neuroinflammation in the aging brain.
  6. The Impact of Senescent Cells on Limb Regeneration.
  7. A Mesenchymal stem cell Aging Framework, from Mechanisms to Strategies.
  8. Young blood-mediated cerebromicrovascular rejuvenation through heterochronic parabiosis: enhancing blood-brain barrier integrity and capillarization in the aged mouse brain.
  9. Aging-regulated PNUTS maintains endothelial barrier function via SEMA3B suppression.
  10. Targeting pathological cells with senolytic drugs reduces seizures in neurodevelopmental mTOR-related epilepsy.
  11. Targeting lysosomal quality control as a therapeutic strategy against aging and diseases.
  12. Gene therapy trials deliver double win.
  13. Non-pituitary growth hormone enables colon cell senescence evasion.
  14. Sulforaphane decreases oxidative stress and inhibits NLRP3 inflammasome activation in a mouse model of ulcerative colitis.
  15. Genome integrity as a potential index of longevity in Ashkenazi Centenarian's families.
  16. Potential Effects of Traditional Chinese Medicine in Anti-Aging and Aging-Related Diseases: Current Evidence and Perspectives.
  17. Tissue-resident C1q + macrophages exert anti-aging potential through the Sirt1 pathway.
  18. Tetrahydroxy stilbene glucoside rejuvenates aging hematopoietic stem cells with predilection for lymphoid differentiation via AMPK and Tet2.
  19. Arachidonic acid in aging: New roles for old players.
  20. Role of umbilical cord mesenchymal stromal cells in skin rejuvenation.
  21. Prokaryotic Argonaute nuclease cooperates with co-encoded RNase to acquire guide RNAs and target invader DNA.
  1. Cell Death Discov. 2024 May 04. 10(1): 217
    Targeting senescent cells with NKG2D-CAR T cells.
    Yushuang Deng, Avadh Kumar, Kan Xie, Kristina Schaaf, Enzo Scifo, Sarah Morsy, Tao Li, Armin Ehninger, Daniele Bano, Dan Ehninger.
      This study investigates the efficacy of NKG2D chimeric antigen receptor (CAR) engineered T cells in targeting and eliminating stress-induced senescent cells in vitro. Cellular senescence contributes to age-related tissue decline and is characterized by permanent cell cycle arrest and the senescence-associated secretory phenotype (SASP). Immunotherapy, particularly CAR-T cell therapy, emerges as a promising approach to selectively eliminate senescent cells. Our focus is on the NKG2D receptor, which binds to ligands (NKG2DLs) upregulated in senescent cells, offering a target for CAR-T cells. Using mouse embryonic fibroblasts (MEFs) and astrocytes (AST) as senescence models, we demonstrate the elevated expression of NKG2DLs in response to genotoxic and oxidative stress. NKG2D-CAR T cells displayed potent cytotoxicity against these senescent cells, with minimal effects on non-senescent cells, suggesting their potential as targeted senolytics. In conclusion, our research presents the first evidence of NKG2D-CAR T cells' ability to target senescent brain cells, offering a novel approach to manage senescence-associated diseases. The findings pave the way for future investigations into the therapeutic applicability of NKG2D-targeting CAR-T cells in naturally aged organisms and models of aging-associated brain diseases in vivo.
    DOI:  https://doi.org/10.1038/s41420-024-01976-7
  2. Aging (Albany NY). 2024 May 09. 16
    Caloric restriction mitigates age-associated senescence characteristics in subcutaneous adipose tissue-derived stem cells.
    Somaiah Chinnapaka, Hamid Malekzadeh, Zayaan Tirmizi, Asim Ejaz.
      Adipose tissue regulates metabolic balance, but aging disrupts it, shifting fat from insulin-sensitive subcutaneous to insulin-resistant visceral depots, impacting overall metabolic health. Adipose-derived stem cells (ASCs) are crucial for tissue regeneration, but aging diminishes their stemness and regeneration potential. Our findings reveal that aging is associated with a decrease in subcutaneous adipose tissue mass and an increase in the visceral fat depots mass. Aging is associated with increase in adipose tissue fibrosis but no significant change in adipocyte size was observed with age. Long term caloric restriction failed to prevent fibrotic changes but resulted in significant decrease in adipocytes size. Aged subcutaneous ASCs displayed an increased production of ROS. Using mitochondrial membrane activity as an indicator of stem cell quiescence and senescence, we observed a significant decrease in quiescence ASCs with age exclusively in subcutaneous adipose depot. In addition, aged subcutaneous adipose tissue accumulated more senescent ASCs having defective autophagy activity. However, long-term caloric restriction leads to a reduction in mitochondrial activity in ASCs. Furthermore, caloric restriction prevents the accumulation of senescent cells and helps retain autophagy activity in aging ASCs. These results suggest that caloric restriction and caloric restriction mimetics hold promise as a potential strategy to rejuvenate the stemness of aged ASCs. Further investigations, including in vivo evaluations using controlled interventions in animals and human studies, will be necessary to validate these findings and establish the clinical potential of this well-established approach for enhancing the stemness of aged stem cells.
    Keywords:  adipose stem cells; adipose tissue; autophagy; caloric restriction; differentiation; reactive oxygen species; senescence; stemness
    DOI:  https://doi.org/10.18632/aging.205812
  3. Food Funct. 2024 May 10.
    From cup to clock: exploring coffee's role in slowing down biological aging.
    Xiaoli Chen, Xin Yin, Yajie Gao, Xin Chen, Nan Ye, Xingkang He.
      Background: Previous research has proposed that coffee consumption may have potential health benefits, yet the effect of coffee on one's biological age has not been determined to date. The purpose of this study is to investigate the influence of coffee drinking on biological aging. Methods: Participants were chosen from the National Health and Nutrition Examination Survey (NHANES) and had to meet the selection criteria. Coffee consumption was evaluated through two 24-hour dietary questionnaires. Biological age was measured using both the PhenoAge and KDM-BA algorithms. Multiple linear and logistic regression models were adopted to analyze the association of coffee consumption with biological aging. Results: A total of 13 384 participants with an average daily coffee consumption of 1.73 cups were included. Participants with higher coffee consumption tended to be older, male, non-Hispanic white; had a higher educational level beyond high school; were more likely to be married; had better financial status; and were less likely to smoke or engage in excessive drinking. These individuals with higher coffee consumption exhibited a younger biological age in relation to their chronological age, as indicated by lower mean advancements in PhenoAge and KDM-BA scores. Furthermore, coffee intake was found to be inversely related to PhenoAge and KDM-BA progressions, as well as to the chances of accelerated biological aging, both in unadjusted and adjusted models. These associations remained consistent across all age and gender groups. Additionally, some heterogeneity was also observed among body mass index and physical activity categories. Conclusions: Coffee drinking was inversely related to biological age advancements and the likelihood of accelerated biological aging. Moderate coffee consumption may offer substantial benefits in reducing biological aging.
    DOI:  https://doi.org/10.1039/d3fo04177h
  4. Nat Aging. 2024 May 09.
    Nature of epigenetic aging from a single-cell perspective.
    Andrei E Tarkhov, Thomas Lindstrom-Vautrin, Sirui Zhang, Kejun Ying, Mahdi Moqri, Bohan Zhang, Alexander Tyshkovskiy, Orr Levy, Vadim N Gladyshev.
      Age-related changes in DNA methylation (DNAm) form the basis of the most robust predictors of age-epigenetic clocks-but a clear mechanistic understanding of exactly which aspects of aging are quantified by these clocks is lacking. Here, to clarify the nature of epigenetic aging, we juxtapose the dynamics of tissue and single-cell DNAm in mice. We compare these changes during early development with those observed during adult aging in mice, and corroborate our analyses with a single-cell RNA sequencing analysis within the same multiomics dataset. We show that epigenetic aging involves co-regulated changes as well as a major stochastic component, and this is consistent with transcriptional patterns. We further support the finding of stochastic epigenetic aging by direct tissue and single-cell DNAm analyses and modeling of aging DNAm trajectories with a stochastic process akin to radiocarbon decay. Finally, we describe a single-cell algorithm for the identification of co-regulated and stochastic CpG clusters showing consistent transcriptomic coordination patterns. Together, our analyses increase our understanding of the basis of epigenetic clocks and highlight potential opportunities for targeting aging and evaluating longevity interventions.
    DOI:  https://doi.org/10.1038/s43587-024-00616-0
  5. Trends Neurosci. 2024 May 09. pii: S0166-2236(24)00061-4. [Epub ahead of print]
    Cellular senescence, DNA damage, and neuroinflammation in the aging brain.
    Wenyan Zhang, Hong-Shuo Sun, Xiaoying Wang, Aaron S Dumont, Qiang Liu.
      Aging may lead to low-level chronic inflammation that increases the susceptibility to age-related conditions, including memory impairment and progressive loss of brain volume. As brain health is essential to promoting healthspan and lifespan, it is vital to understand age-related changes in the immune system and central nervous system (CNS) that drive normal brain aging. However, the relative importance, mechanistic interrelationships, and hierarchical order of such changes and their impact on normal brain aging remain to be clarified. Here, we synthesize accumulating evidence that age-related DNA damage and cellular senescence in the immune system and CNS contribute to the escalation of neuroinflammation and cognitive decline during normal brain aging. Targeting cellular senescence and immune modulation may provide a logical rationale for developing new treatment options to restore immune homeostasis and counteract age-related brain dysfunction and diseases.
    Keywords:  brain aging; brain barriers; immunity; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.1016/j.tins.2024.04.003
  6. Cell Reprogram. 2024 May 07.
    The Impact of Senescent Cells on Limb Regeneration.
    Marlene J Oesterle, Nicholas D Leigh.
      Cellular senescence is a state in which cells enter cell cycle arrest. However, senescent cells have the ability to secrete signaling molecules such as chemokines, cytokines, and growth factors. This secretory activity is an important feature of senescent cells, since the secreted factors impact the surrounding cellular microenvironment. Indeed, senescent cells and their secretome play a crucial role during limb development. However, whether the process of limb regeneration also relies on senescent cells remains unclear. Creation of a novel targeted depletion strategy that can eliminate senescent cells in the regenerating limb has now demonstrated an important role for senescent cells in limb regeneration. This role is linked to senescent cell-derived Wnt signaling. These findings reveal a previously unknown role for senescent cells during limb regeneration through Wnt signaling.
    Keywords:  complex tissue regeneration; limb regeneration; senescent cells
    DOI:  https://doi.org/10.1089/cell.2024.0021
  7. Stem Cell Rev Rep. 2024 May 10.
    A Mesenchymal stem cell Aging Framework, from Mechanisms to Strategies.
    Hongqing Zhao, Houming Zhao, Shuaifei Ji.
      Mesenchymal stem cells (MSCs) are extensively researched for therapeutic applications in tissue engineering and show significant potential for clinical use. Intrinsic or extrinsic factors causing senescence may lead to reduced proliferation, aberrant differentiation, weakened immunoregulation, and increased inflammation, ultimately limiting the potential of MSCs. It is crucial to comprehend the molecular pathways and internal processes responsible for the decline in MSC function due to senescence in order to devise innovative approaches for rejuvenating senescent MSCs and enhancing MSC treatment. We investigate the main molecular processes involved in senescence, aiming to provide a thorough understanding of senescence-related issues in MSCs. Additionally, we analyze the most recent advancements in cutting-edge approaches to combat MSC senescence based on current research. We are curious whether the aging process of stem cells results in a permanent "memory" and if cellular reprogramming may potentially revert the aging epigenome to a more youthful state.
    Keywords:  Mesenchymal stem cells; Rejuvenation; Senescence
    DOI:  https://doi.org/10.1007/s12015-024-10732-4
  8. Geroscience. 2024 May 10.
    Young blood-mediated cerebromicrovascular rejuvenation through heterochronic parabiosis: enhancing blood-brain barrier integrity and capillarization in the aged mouse brain.
    Rafal Gulej, Ádám Nyúl-Tóth, Boglarka Csik, Roland Patai, Benjamin Petersen, Sharon Negri, Siva Sai Chandragiri, Santny Shanmugarama, Peter Mukli, Andriy Yabluchanskiy, Shannon Conley, Derek Huffman, Stefano Tarantini, Anna Csiszar, Zoltan Ungvari.
      Age-related cerebromicrovascular changes, including blood-brain barrier (BBB) disruption and microvascular rarefaction, play a significant role in the development of vascular cognitive impairment (VCI) and neurodegenerative diseases. Utilizing the unique model of heterochronic parabiosis, which involves surgically joining young and old animals, we investigated the influence of systemic factors on these vascular changes. Our study employed heterochronic parabiosis to explore the effects of young and aged systemic environments on cerebromicrovascular aging in mice. We evaluated microvascular density and BBB integrity in parabiotic pairs equipped with chronic cranial windows, using intravital two-photon imaging techniques. Our results indicate that short-term exposure to young systemic factors leads to both functional and structural rejuvenation of cerebral microcirculation. Notably, we observed a marked decrease in capillary density and an increase in BBB permeability to fluorescent tracers in the cortices of aged mice undergoing isochronic parabiosis (20-month-old C57BL/6 mice [A-(A)]; 6 weeks of parabiosis), compared to young isochronic parabionts (6-month-old, [Y-(Y)]). However, aged heterochronic parabionts (A-(Y)) exposed to young blood exhibited a significant increase in cortical capillary density and restoration of BBB integrity. In contrast, young mice exposed to old blood from aged parabionts (Y-(A)) rapidly developed cerebromicrovascular aging traits, evidenced by reduced capillary density and increased BBB permeability. These findings underscore the profound impact of systemic factors in regulating cerebromicrovascular aging. The rejuvenation observed in the endothelium, following exposure to young blood, suggests the existence of anti-geronic elements that counteract microvascular aging. Conversely, pro-geronic factors in aged blood appear to accelerate cerebromicrovascular aging. Further research is needed to assess whether the rejuvenating effects of young blood factors could extend to other age-related cerebromicrovascular pathologies, such as microvascular amyloid deposition and increased microvascular fragility.
    Keywords:  Aging; Alzheimer’s disease; Blood-brain barrier; Brain aging; Cerebromicrovascular aging; Cognitive health; Microvascular density; Systemic milieu; VCID
    DOI:  https://doi.org/10.1007/s11357-024-01154-8
  9. Commun Biol. 2024 May 07. 7(1): 541
    Aging-regulated PNUTS maintains endothelial barrier function via SEMA3B suppression.
    Noelia Lozano-Vidal, Laura Stanicek, Diewertje I Bink, Rio P Juni, Aukie Hooglugt, Veerle Kremer, Philippa Phelp, Anke van Bergen, Alyson W MacInnes, Stefanie Dimmeler, Reinier A Boon.
      Age-related diseases pose great challenges to health care systems worldwide. During aging, endothelial senescence increases the risk for cardiovascular disease. Recently, it was described that Phosphatase 1 Nuclear Targeting Subunit (PNUTS) has a central role in cardiomyocyte aging and homeostasis. Here, we determine the role of PNUTS in endothelial cell aging. We confirm that PNUTS is repressed in senescent endothelial cells (ECs). Moreover, PNUTS silencing elicits several of the hallmarks of endothelial aging: senescence, reduced angiogenesis and loss of barrier function. Findings are validate in vivo using endothelial-specific inducible PNUTS-deficient mice (Cdh5-CreERT2;PNUTSfl/fl), termed PNUTSEC-KO. Two weeks after PNUTS deletion, PNUTSEC-KO mice present severe multiorgan failure and vascular leakage. Transcriptomic analysis of PNUTS-silenced HUVECs and lungs of PNUTSEC-KO mice reveal that the PNUTS-PP1 axis tightly regulates the expression of semaphorin 3B (SEMA3B). Indeed, silencing of SEMA3B completely restores barrier function after PNUTS loss-of-function. These results reveal a pivotal role for PNUTS in endothelial homeostasis through a SEMA3B downstream pathway that provides a potential target against the effects of aging in ECs.
    DOI:  https://doi.org/10.1038/s42003-024-06230-5
  10. Nat Neurosci. 2024 May 06.
    Targeting pathological cells with senolytic drugs reduces seizures in neurodevelopmental mTOR-related epilepsy.
    Théo Ribierre, Alexandre Bacq, Florian Donneger, Marion Doladilhe, Marina Maletic, Delphine Roussel, Isabelle Le Roux, Francine Chassoux, Bertrand Devaux, Homa Adle-Biassette, Sarah Ferrand-Sorbets, Georg Dorfmüller, Mathilde Chipaux, Sara Baldassari, Jean-Christophe Poncer, Stéphanie Baulac.
      Cortical malformations such as focal cortical dysplasia type II (FCDII) are associated with pediatric drug-resistant epilepsy that necessitates neurosurgery. FCDII results from somatic mosaicism due to post-zygotic mutations in genes of the PI3K-AKT-mTOR pathway, which produce a subset of dysmorphic cells clustered within healthy brain tissue. Here we show a correlation between epileptiform activity in acute cortical slices obtained from human surgical FCDII brain tissues and the density of dysmorphic neurons. We uncovered multiple signatures of cellular senescence in these pathological cells, including p53/p16 expression, SASP expression and senescence-associated β-galactosidase activity. We also show that administration of senolytic drugs (dasatinib/quercetin) decreases the load of senescent cells and reduces seizure frequency in an MtorS2215F FCDII preclinical mouse model, providing proof of concept that senotherapy may be a useful approach to control seizures. These findings pave the way for therapeutic strategies selectively targeting mutated senescent cells in FCDII brain tissue.
    DOI:  https://doi.org/10.1038/s41593-024-01634-2
  11. Med Res Rev. 2024 May 06.
    Targeting lysosomal quality control as a therapeutic strategy against aging and diseases.
    Yuchen He, Yishu Fan, Xenab Ahmadpoor, Yumin Wang, Zhong Alan Li, Weihong Zhu, Hang Lin.
      Previously, lysosomes were primarily referred to as the digestive organelles and recycling centers within cells. Recent discoveries have expanded the lysosomal functional scope and revealed their critical roles in nutrient sensing, epigenetic regulation, plasma membrane repair, lipid transport, ion homeostasis, and cellular stress response. Lysosomal dysfunction is also found to be associated with aging and several diseases. Therefore, function of macroautophagy, a lysosome-dependent intracellular degradation system, has been identified as one of the updated twelve hallmarks of aging. In this review, we begin by introducing the concept of lysosomal quality control (LQC), which is a cellular machinery that maintains the number, morphology, and function of lysosomes through different processes such as lysosomal biogenesis, reformation, fission, fusion, turnover, lysophagy, exocytosis, and membrane permeabilization and repair. Next, we summarize the results from studies reporting the association between LQC dysregulation and aging/various disorders. Subsequently, we explore the emerging therapeutic strategies that target distinct aspects of LQC for treating diseases and combatting aging. Lastly, we underscore the existing knowledge gap and propose potential avenues for future research.
    Keywords:  aging; autoimmune diseases; cancer; degenerative diseases; lysosomal quality control
    DOI:  https://doi.org/10.1002/med.22047
  12. Nat Med. 2024 May 09.
    Gene therapy trials deliver double win.
    Karen O'Leary.
      
    Keywords:  Clinical trials; Gene therapy
    DOI:  https://doi.org/10.1038/d41591-024-00033-1
  13. Aging Cell. 2024 May 09. e14193
    Non-pituitary growth hormone enables colon cell senescence evasion.
    Vera Chesnokova, Svetlana Zonis, Tugce Apaydin, Robert Barrett, Shlomo Melmed.
      DNA damage-induced senescence is initially sustained by p53. Senescent cells produce a senescence-associated secretory phenotype (SASP) that impacts the aging microenvironment, often promoting cell transformation. Employing normal non-tumorous human colon cells (hNCC) derived from surgical biopsies and three-dimensional human intestinal organoids, we show that local non-pituitary growth hormone (npGH) induced in senescent cells is a SASP component acting to suppress p53. npGH autocrine/paracrine suppression of p53 results in senescence evasion and cell-cycle reentry, as evidenced by increased Ki67 and BrdU incorporation. Post-senescent cells exhibit activated epithelial-to-mesenchymal transition (EMT), and increased cell motility. Nu/J mice harboring GH-secreting HCT116 xenografts with resultant high GH levels and injected intrasplenic with post-senescent hNCC developed fourfold more metastases than did mice harboring control xenografts, suggesting that paracrine npGH enables post-senescent cell transformation. By contrast, senescent cells with suppressed npGH exhibit downregulated Ki67 and decreased soft agar colony formation. Mechanisms underlying these observations include npGH induction by the SASP chemokine CXCL1, which attracts immune effectors to eliminate senescent cells; GH, in turn, suppresses CXCL1, likely by inhibiting phospho-NFκB, resulting in SASP cytokine downregulation. Consistent with these findings, GH-receptor knockout mice exhibited increased colon phospho-NFκB and CXCL1, while GH excess decreased colon CXCL1. The results elucidate mechanisms for local hormonal regulation of microenvironmental changes in DNA-damaged non-tumorous epithelial cells and portray a heretofore unappreciated GH action favoring age-associated epithelial cell transformation.
    Keywords:  DNA damage; growth hormone; senescence‐associated secretory phenotype
    DOI:  https://doi.org/10.1111/acel.14193
  14. Biomed Pharmacother. 2024 May 06. pii: S0753-3322(24)00590-0. [Epub ahead of print]175 116706
    Sulforaphane decreases oxidative stress and inhibits NLRP3 inflammasome activation in a mouse model of ulcerative colitis.
    Zi-Juan Zhou, Jian-Yi Dong, Yang Qiu, Guo-Lin Zhang, Kun Wei, Li-Heng He, Yi-Ning Sun, Hao-Zheng Jiang, Shuang-Shuang Zhang, Xin-Rui Guo, Jing-Yu Wang, Da-Peng Chen.
      Excessive oxidative stress and NLRP3 inflammasome activation are considered the main drivers of inflammatory bowel disease (IBD), and inhibition of inflammasomes ameliorates clinical symptoms and morphological manifestations of IBD. Herein, we examined the roles of NLRP3 activation in IBD and modulation of NLRP3 by sulforaphane (SFN), a compound with multiple pharmacological activities that is extracted from cruciferous plants. To simulate human IBD, we established a mouse colitis model by administering dextran sodium sulfate in the drinking water. SFN (25, 50 mg·kg-1·d-1, ig) or the positive control sulfasalazine (500 mg/kg, ig) was administered to colitis-affected mice for 7 days. Model mice displayed pathological alterations in colon tissue as well as classic symptoms of colitis beyond substantial tissue inflammation. Expression of NLRP3, ASC, and caspase-1 was significantly elevated in the colonic epithelium. The expression of NLRP3 inflammasomes led to activation of downstream proteins and increases in the cytokines IL-18 and IL-1β. SFN administration either fully or partially reversed these changes, thus restoring IL-18 and IL-1β, substantially inhibiting NLRP3 activation, and decreasing inflammation. SFN alleviated the inflammation induced by LPS and NLRP3 agonists in RAW264.7 cells by decreasing the levels of reactive oxygen species. In summary, our results revealed the pathological roles of oxidative stress and NLRP3 in colitis, and indicated that SFN might serve as a natural NLRP3 inhibitor, thereby providing a new strategy for alternative colitis treatment.
    Keywords:  Food function; Inflammatory bowel disease; NLRP3 inflammasomes; Reactive oxygen species; Sulforaphane
    DOI:  https://doi.org/10.1016/j.biopha.2024.116706
  15. Geroscience. 2024 May 09.
    Genome integrity as a potential index of longevity in Ashkenazi Centenarian's families.
    Mariana Andrawus, Gil Ben David, Ivana Terziyska, Lital Sharvit, Aviv Bergman, Nir Barzilai, Srilakshmi M Raj, Diddahally R Govindaraju, Gil Atzmon.
      The aging process, or senescence, is characterized by age-specific decline in physical and physiological function, and increased frailty and genomic changes, including mutation accumulation. However, the mechanisms through which changes in genomic architecture influence human longevity have remained obscure. Copy number variants (CNVs), an abundant class of genomic variants, offer unique opportunities for understanding age-related genomic changes. Here we report the spectrum of CNVs in a cohort of 670 Ashkenazi Jewish centenarians, their progeny, and unrelated controls. The average ages of these groups were 97.4 ± 2.8, 69.2 ± 9.2, and 66.5 ± 7.0 respectively. For the first time, we compared different size classes of CNVs, from 1 kB to 100 MB in size. Using a high-resolution custom Affymetrix array, targeting 44,639 genomic regions, we identified a total of 12,166, 22,188, and 10,285 CNVs in centenarians, their progeny, and control groups, respectively. Interestingly, the offspring group showed the highest number of unique CNVs, followed by control and centenarians. While both gains and losses were found in all three groups, centenarians showed a significantly higher average number of both total gains and losses relative to their controls (p < 0.0327, 0.0182, respectively). Moreover, centenarians showed a lower total length of genomic material lost, suggesting that they may maintain superior genomic integrity over time. We also observe a significance fold increase of CNVs among the offspring, implying greater genomic integrity and a putative mechanism for longevity preservation. Genomic regions that experienced loss or gains appear to be distributed across many sites in the genome and contain genes involved in DNA transcription, cellular transport, developmental pathways, and metabolic functions. Our findings suggest that the exceptional longevity observed in centenarians may be attributed to the prolonged maintenance of functionally important genes. These genes are intrinsic to specific genomic regions as well as to the overall integrity of the genomic architecture. Additionally, a strong association between longer CNVs and differential gene expression observed in this study supports the notion that genomic integrity could positively influence longevity.
    Keywords:  Centenarians; Copy number variants; Genome plasticity; Senescence
    DOI:  https://doi.org/10.1007/s11357-024-01178-0
  16. Clin Interv Aging. 2024 ;19 681-693
    Potential Effects of Traditional Chinese Medicine in Anti-Aging and Aging-Related Diseases: Current Evidence and Perspectives.
    Xue Ding, Xiuxia Ma, Pengfei Meng, Jingyu Yue, Liangping Li, Liran Xu.
      Aging and aging-related diseases present a global public health problem. Therefore, the development of efficient anti-aging drugs has become an important area of research. Traditional Chinese medicine is an important complementary and alternative branch of aging-related diseases therapy. Recently, a growing number of studies have revealed that traditional Chinese medicine has a certain delaying effect on the progression of aging and aging-related diseases. Here, we review the progress in research into using traditional Chinese medicine for aging and aging-related diseases (including neurodegenerative diseases, cardiovascular diseases, diabetes, and cancer). Furthermore, we summarize the potential mechanisms of action of traditional Chinese medicine and provide references for further studies on aging and aging-related diseases.
    Keywords:  aging and aging-related diseases; potential mechanisms; traditional Chinese medicine
    DOI:  https://doi.org/10.2147/CIA.S447514
  17. Inflamm Res. 2024 May 09.
    Tissue-resident C1q + macrophages exert anti-aging potential through the Sirt1 pathway.
    Liang Liu, Lingjuan Zhu, Qian Liang, Lingling Yu, Longlong Hu, Yun Yu, Xiaoshu Cheng, Huihui Bao.
      OBJECTIVE: Resident immune cells are at the forefront of sensory organ-specific signals, and changes in these cells are closely related to the aging process. The Sirt pathway can regulate NAD + metabolism during aging, thereby affecting the accumulation of ROS. However, the role of the Sirt pathway in resident immune cells in aged tissues is currently unclear.METHODS: We investigated Sirt1 signalling in resident immune cells during chronic inflammation in an aged mouse model. Integrated single-cell RNA sequencing data from young and aged mice were used to refine the characterization of immune cells in aged tissues RESULTS: We found that C1q + macrophages could affect chronic inflammation during aging. C1q + macrophages acted in an opposing manner to Il1b + macrophages and were responsible for anti-inflammatory effects during aging. Sirt1 agonists inhibited the decrease in C1qb in macrophages during aging, and anti-aging drugs could affect the expression of C1qb in macrophages via the Sirt1 pathway.
    CONCLUSIONS: In this study, we first identified the relevance of C1q + macrophages in chronic inflammation during aging. The potential anti-aging effect of C1q + macrophages was mediated by the Sirt1 pathway, suggesting new strategies for aging immunotherapy.
    Keywords:  Anti-aging; Immune cells; Inflammation; Macrophages; Sirt1 pathway
    DOI:  https://doi.org/10.1007/s00011-024-01883-8
  18. J Adv Res. 2024 May 03. pii: S2090-1232(24)00170-X. [Epub ahead of print]
    Tetrahydroxy stilbene glucoside rejuvenates aging hematopoietic stem cells with predilection for lymphoid differentiation via AMPK and Tet2.
    Dan Gao, Wei-Wei Yi, Bo Liu, Cong-En Zhang, Cui-Cui Yang, Li Zeng, Lin Li, Guangbin Luo, Lan Zhang, Zhen-Yu Ju, Jia-Bo Wang.
      INTRODUCTION: Aging of hematopoietic stem cells (HSCs) has emerged as an important challenge to human health. Recent advances have raised the prospect of rejuvenating aging HSCs via specific medical interventions, including pharmacological treatments. Nonetheless, efforts to develop such drugs are still in infancy until now.OBJECTIVES: We aimed to screen the prospective agents that can rejuvenate aging HSCs and explore the potential mechanisms.
    METHODS: We screened a set of natural anti-aging compounds through oral administration to sub-lethally irradiated mice, and identified 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) as a potent rejuvenating agent for aging HSCs. Then naturally aged mice were used for the follow-up assessment to determine the HSC rejuvenating potential of TSG. Finally, based on the transcriptome and DNA methylation analysis, we validated the role of the AMP-activated protein kinase (AMPK)-ten-eleven-translocation 2 (Tet2) axis (the AMPK-Tet2 axis) as the underlying mechanisms of TSG for ameliorating HSCs aging.
    RESULTS: TSG treatment not only significantly increased the absolute number of common lymphoid progenitors (CLPs) along with B lymphocytes, but also boosted the HSCs/CLPs repopulation potential of aging mice. Further elaborated mechanism research demonstrated that TSG supplementation restored the stemness of aging HSCs, as well as promoted an epigenetic reprograming that was associated with an improved regenerative capacity and an increased rate of lymphopoiesis. Such effects were diminished when the mice were co-treated with an AMPK inhibitor, or when it was performed in Tet2 knockout mice as well as senescent cells assay.
    CONCLUSION: TSG is effective in rejuvenating aging HSCs by modulating the AMPK- Tet2 axis and thus represents a potential candidate for developing effective HSC rejuvenating therapies.
    Keywords:  AMPK-Tet2 axis; Aging; Hematopoietic stem cells; Lymphoid differentiation; Tetrahydroxy stilbene glucoside
    DOI:  https://doi.org/10.1016/j.jare.2024.04.027
  19. J Adv Res. 2024 May 04. pii: S2090-1232(24)00180-2. [Epub ahead of print]
    Arachidonic acid in aging: New roles for old players.
    Chen Qian, Qing Wang, Yusen Qiao, Ze Xu, Linlin Zhang, Haixiang Xiao, Zhixiang Lin, Mingzhou Wu, Wenyu Xia, Huilin Yang, Jiaxiang Bai, Dechun Geng.
      BACKGROUND: Arachidonic acid (AA), one of the most ubiquitous polyunsaturated fatty acids (PUFAs), provides fluidity to mammalian cell membranes. It is derived from linoleic acid (LA) and can be transformed into various bioactive metabolites, including prostaglandins (PGs), thromboxanes (TXs), lipoxins (LXs), hydroxy-eicosatetraenoic acids (HETEs), leukotrienes (LTs), and epoxyeicosatrienoic acids (EETs), by different pathways. All these processes are involved in AA metabolism. Currently, in the context of an increasingly visible aging world population, several scholars have revealed the essential role of AA metabolism in osteoporosis, chronic obstructive pulmonary disease, and many other aging diseases.AIM OF REVIEW: Although there are some reviews describing the role of AA in some specific diseases, there seems to be no or little information on the role of AA metabolism in aging tissues or organs. This review scrutinizes and highlights the role of AA metabolism in aging and provides a new idea for strategies for treating aging-related diseases.
    KEY SCIENTIFIC CONCEPTS OF REVIEW: As a member of lipid metabolism, AA metabolism regulates the important lipids that interfere with the aging in several ways. We present a comprehensivereviewofthe role ofAA metabolism in aging, with the aim of relieving the extreme suffering of families and the heavy economic burden on society caused by age-related diseases. We also collected and summarized data on anti-aging therapies associated with AA metabolism, with the expectation of identifying a novel and efficient way to protect against aging.
    Keywords:  Aging; Aging diseases; Arachidonic acid; Therapeutic strategies
    DOI:  https://doi.org/10.1016/j.jare.2024.05.003
  20. NPJ Regen Med. 2024 May 10. 9(1): 20
    Role of umbilical cord mesenchymal stromal cells in skin rejuvenation.
    Le Chang, Wei-Wen Fan, He-Ling Yuan, Xin Liu, Qiang Wang, Guang-Ping Ruan, Xing-Hua Pan, Xiang-Qing Zhu.
      Aging is the main cause of many degenerative diseases. The skin is the largest and the most intuitive organ that reflects the aging of the body. Under the interaction of endogenous and exogenous factors, there are cumulative changes in the structure, function, and appearance of the skin, which are characterized by decreased synthesis of collagen and elastin, increased wrinkles, relaxation, pigmentation, and other aging characteristics. skin aging is inevitable, but it can be delayed. The successful isolation of mesenchymal stromal cells (MSC) in 1991 has greatly promoted the progress of cell therapy in human diseases. The International Society for Cellular Therapy (ISCT) points out that the MSC is a kind of pluripotent progenitor cells that have self-renewal ability (limited) in vitro and the potential for mesenchymal cell differentiation. This review mainly introduces the role of perinatal umbilical cord-derived MSC(UC-MSC) in the field of skin rejuvenation. An in-depth and systematic understanding of the mechanism of UC-MSCs against skin aging is of great significance for the early realization of the clinical transformation of UC-MSCs. This paper summarized the characteristics of skin aging and summarized the mechanism of UC-MSCs in skin rejuvenation reported in recent years. In order to provide a reference for further research of UC-MSCs to delay skin aging.
    DOI:  https://doi.org/10.1038/s41536-024-00363-1
  21. Nucleic Acids Res. 2024 May 08. pii: gkae345. [Epub ahead of print]
    Prokaryotic Argonaute nuclease cooperates with co-encoded RNase to acquire guide RNAs and target invader DNA.
    Aleksei Agapov, Vladimir Panteleev, Ekaterina Kropocheva, Anna Kanevskaya, Daria Esyunina, Andrey Kulbachinskiy.
      Argonautes are an evolutionary conserved family of programmable nucleases that identify target nucleic acids using small guide oligonucleotides. In contrast to eukaryotic Argonautes (eAgos) that act on RNA, most studied prokaryotic Argonautes (pAgos) recognize DNA targets. Similarly to eAgos, pAgos can protect prokaryotic cells from invaders, but the biogenesis of guide oligonucleotides that confer them specificity to their targets remains poorly understood. Here, we have identified a new group of RNA-guided pAgo nucleases and demonstrated that a representative pAgo from this group, AmAgo from the mesophilic bacterium Alteromonas macleodii, binds guide RNAs of varying lengths for specific DNA targeting. Unlike most pAgos and eAgos, AmAgo is strictly specific to hydroxylated RNA guides containing a 5'-adenosine. AmAgo and related pAgos are co-encoded with a conserved RNA endonuclease from the HEPN superfamily (Ago-associated protein, Agap-HEPN). In vitro, Agap cleaves RNA between guanine and adenine nucleotides producing hydroxylated 5'-A guide oligonucleotides bound by AmAgo. In vivo, Agap cooperates with AmAgo in acquiring guide RNAs and counteracting bacteriophage infection. The AmAgo-Agap pair represents the first example of a pAgo system that autonomously produces RNA guides for DNA targeting and antiviral defense, which holds promise for programmable DNA targeting in biotechnology.
    DOI:  https://doi.org/10.1093/nar/gkae345
This page is being maintained by Thomas Krichel. It was last updated on 2024‒05‒20 at 3:29.