bims-caglex Biomed News
on Cellular aging and life extension
Issue of 2024‒06‒30
forty-six papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño
  1. Arctigenin from Fructus arctii Exhibits Antiaging Effects via Autophagy Induction, Antioxidative Stress, and Increase in Telomerase Activity in Yeast.
  2. β-Cyclocitral from Lavandula angustifolia Mill. Exerts Anti-Aging Effects on Yeasts and Mammalian Cells via Telomere Protection, Antioxidative Stress, and Autophagy Activation.
  3. Oral Administration of Nacre Extract from Pearl Oyster Shells Has Anti-Aging Effects on Skin and Muscle, and Extends the Lifespan in SAMP8 Mice.
  4. SVHRSP Alleviates Age-Related Cognitive Deficiency by Reducing Oxidative Stress and Neuroinflammation.
  5. [Transition metal accumulation and cellular senescence].
  6. Senescent cell-derived vaccines: a new concept towards an immune response against cancer and aging?
  7. TERT activation targets DNA methylation and multiple aging hallmarks.
  8. Adoptive NK cell therapy: a potential revolutionary approach in longevity therapeutics.
  9. Aging and homeostasis of the hypodermis in the age-related deterioration of skin function.
  10. Human Aging and Age-Related Diseases: From Underlying Mechanisms to Pro-Longevity Interventions.
  11. The anti-aging effects of Chlorella polysaccharide extract in Caenorhabditis elegans.
  12. Biomarkers of Cellular Senescence and Aging: Current State-of-the-Art, Challenges and Future Perspectives.
  13. Improvement in Epigenetic Aging Clock Induced by BioBran Containing Rice Kefiran in Relation to Various Biomarkers: A Pilot Study.
  14. Exogenous Nucleotides Improve the Skin Aging of SAMP8 Mice by Modulating Autophagy through MAPKs and AMPK Pathways.
  15. Adipose-Derived Mesenchymal Stem Cells and Their Derived Epidermal Progenitor Cells Conditioned Media Ameliorate Skin Aging in Rats.
  16. HUMAN CST STIMULATES BASE EXCISION REPAIR TO PREVENT THE ACCUMULATION OF OXIDATIVE DNA DAMAGE.
  17. Involvement of Matricellular Proteins in Cellular Senescence: Potential Therapeutic Targets for Age-Related Diseases.
  18. A mechanism for telomere-specific telomere length regulation.
  19. Towards Healthy Longevity: Comprehensive Insights from Molecular Targets and Biomarkers to Biological Clocks.
  20. Small molecule telomerase inhibitors are also potent inhibitors of telomeric C-strand synthesis.
  21. Lack of T04C9.1, the Homologue of Mammalian APPL2, Leads to Premature Ageing and Shortens Lifespan in Caenorhabditis elegans.
  22. DNA methylation as an epigenetic mechanism in the regulation of LEDGF expression and biological response in aging and oxidative stress.
  23. Endothelial cellular senescence and tau accumulation: An interplay full of opportunities?
  24. Role of Mesenchymal Stem/Stromal Cells (MSCs) and MSC-Derived Extracellular Vesicles (EVs) in Prevention of Telomere Length Shortening, Cellular Senescence, and Accelerated Biological Aging.
  25. Artesunate Exerts Organ- and Tissue-Protective Effects by Regulating Oxidative Stress, Inflammation, Autophagy, Apoptosis, and Fibrosis: A Review of Evidence and Mechanisms.
  26. Revitalizing the Aging Immune System Through Selective Stem Cell Targeting.
  27. Role of mitochondrial homeostasis in D-galactose-induced cardiovascular ageing from bench to bedside.
  28. Stem cell-derived extracellular vesicles as senotherapeutics.
  29. The Influence of Aging on the Unfolded Protein Response in Human Skeletal Muscle at Rest and Following Acute Exercise.
  30. fmo-4 promotes longevity and stress resistance via ER to mitochondria calcium regulation in C. elegans.
  31. m6A Reader HNRNPC Facilitates Adipogenesis by Regulating Cytoskeletal Remodeling through Enhanced Lcp1 mRNA Stability.
  32. Aerobic exercise suppresses CCN2 secretion from senescent muscle stem cells and boosts muscle regeneration in aged mice.
  33. A second generation of senotherapies: the development of targeted senolytics, senoblockers and senoreversers for healthy ageing.
  34. In Vivo Proximity Labeling Identifies a New Function for the Lifespan and Autophagy-regulating Kinase Pef1, an Ortholog of Human Cdk5.
  35. Investigating hormesis, aging, and neurodegeneration: From bench to clinics.
  36. Renin-angiotensin system inhibitors positively impact on multiple aging regulatory pathways: Could they be used to protect against human aging?
  37. Molecular and Evolutionary Analysis of RNA-Protein Interactions in Telomerase Regulation.
  38. Role of Adipose-Derived Mesenchymal Stem Cells in Bone Regeneration.
  39. Organic light-emitting diode therapy promotes longevity through the upregulation of SIRT1 in senescence-accelerated mouse prone 8 mice.
  40. Development of a versatile optical pH sensor array for discrimination of anti-aging face creams.
  41. Highly efficient and specific regulation of gene expression using enhanced CRISPR-Cas12f system.
  42. Nicotinamide N-Methyltransferase (NNMT): A New Hope for Treating Aging and Age-Related Conditions.
  43. Comparison of Age-Related Decline and Behavioral Validity in C57BL/6 and CB6F1 Mice.
  44. Cellular Aging and Senescence in Cancer: A Holistic Review of Cellular Fate Determinants.
  45. Tracking DOT1L methyltransferase activity by stable isotope labelling using a selective synthetic co-factor.
  46. Discovering fragile clades and causal sequences in phylogenomics by evolutionary sparse learning.
  1. Antioxidants (Basel). 2024 Jun 02. pii: 684. [Epub ahead of print]13(6):
    Arctigenin from Fructus arctii Exhibits Antiaging Effects via Autophagy Induction, Antioxidative Stress, and Increase in Telomerase Activity in Yeast.
    Siqi Chen, Yajing Li, Enchan Wu, Qing Li, Lan Xiang, Jianhua Qi.
      Aging is often accompanied by irreversible decline in body function, which causes a large number of age-related diseases and brings a huge economic burden to society and families. Many traditional Chinese medicines have been known to extend lifespan, but it has still been a challenge to isolate a single active molecule from them and verify the mechanism of anti-aging action. Drugs that inhibit senescence-associated secretory phenotypes (SASPs) are called "senomorphics". In this study, arctigenin (ATG), a senomorphic, was screened from the Chinese medicine Fructus arctii using K6001 yeast replicative lifespan. Autophagy, oxidative stress, and telomerase activity are key mechanisms related to aging. We found that ATG may act through multiple mechanisms to become an effective anti-aging molecule. In exploring the effect of ATG on autophagy, it was clearly observed that ATG significantly enhanced autophagy in yeast. We further verified that ATG can enhance autophagy by targeting protein phosphatase 2A (PP2A), leading to an increased lifespan. Meanwhile, we evaluated the antioxidant capacity of ATG and found that ATG increased the activities of the antioxidant enzymes, thereby reducing reactive oxygen species (ROS) and malondialdehyde (MDA) levels to improve the survival of yeast under oxidative stress. In addition, ATG was able to increase telomerase activity by enhancing the expression of EST1, EST2, and EST3 genes in yeast. In conclusion, ATG exerts anti-aging effects through induction of autophagy, antioxidative stress, and enhancement of telomerase activity in yeast, which is recognized as a potential molecule with promising anti-aging effects, deserving in-depth research in the future.
    Keywords:  Fructus arctii; antioxidative stress; arctigenin; autophagy; lifespan; telomerase activity
    DOI:  https://doi.org/10.3390/antiox13060684
  2. Antioxidants (Basel). 2024 Jun 12. pii: 715. [Epub ahead of print]13(6):
    β-Cyclocitral from Lavandula angustifolia Mill. Exerts Anti-Aging Effects on Yeasts and Mammalian Cells via Telomere Protection, Antioxidative Stress, and Autophagy Activation.
    Jiaheng Shan, Jianxia Mo, Chenyue An, Lan Xiang, Jianhua Qi.
      We used a replicative lifespan (RLS) experiment of K6001 yeast to screen for anti-aging compounds within lavender extract (Lavandula angustifolia Mill.), leading to the discovery of β-cyclocitral (CYC) as a potential anti-aging compound. Concurrently, the chronological lifespan (CLS) of YOM36 yeast and mammalian cells confirmed the anti-aging effect of CYC. This molecule extended the yeast lifespan and inhibited etoposide (ETO)-induced cell senescence. To understand the mechanism of CYC, we analyzed its effects on telomeres, oxidative stress, and autophagy. CYC administration resulted in notable increases in the telomerase content, telomere length, and the expression of the telomeric shelterin protein components telomeric-repeat binding factor 2 (TRF2) and repressor activator protein 1 (RAP1). More interestingly, CYC reversed H2O2-induced telomere damage and exhibited strong antioxidant capacity. Moreover, CYC improved the survival rate of BY4741 yeast under oxidative stress induced by 6.2 mM H2O2, increasing the antioxidant enzyme activity while reducing the reactive oxygen species (ROS), reactive nitrogen species (RNS), and malondialdehyde (MDA) levels. Additionally, CYC enhanced autophagic flux and free green fluorescent protein (GFP) expression in the YOM38-GFP-ATG8 yeast strain. However, CYC did not extend the RLS of K6001 yeast mutants, such as Δsod1, Δsod2, Δcat, Δgpx, Δatg2, and Δatg32, which lack antioxidant enzymes or autophagy-related genes. These findings reveal that CYC acts as an anti-aging agent by modifying telomeres, oxidative stress, and autophagy. It is a promising compound with potential anti-aging effects and warrants further study.
    Keywords:  Lavandula angustifolia Mill.; anti-aging; antioxidative stress; autophagy; telomere protection; β-cyclocitral
    DOI:  https://doi.org/10.3390/antiox13060715
  3. Pharmaceuticals (Basel). 2024 May 31. pii: 713. [Epub ahead of print]17(6):
    Oral Administration of Nacre Extract from Pearl Oyster Shells Has Anti-Aging Effects on Skin and Muscle, and Extends the Lifespan in SAMP8 Mice.
    Hana Yamamoto, Nanami Shimomura, Yasushi Hasegawa.
      Pearl oysters have been extensively utilized in pearl production; however, most pearl oyster shells are discarded as industrial waste. In a previous study, we demonstrated that the intraperitoneal administration of pearl oyster shell-derived nacre extract (NE) prevented d-galactose-induced brain and skin aging. In this study, we examined the anti-aging effects of orally administered NE in senescence-accelerated mice (SAMP8). Feeding SAMP8 mice NE prevented the development of aging-related characteristics, such as coarse and dull hair, which are commonly observed in aged mice. Additionally, the NE mitigated muscle aging in SAMP8 mice, such as a decline in grip strength. Histological analysis of skeletal muscle revealed that the NE suppressed the expression of aging markers, cyclin-dependent kinase inhibitor 2A (p16) and cyclin-dependent kinase inhibitor 1 (p21), and increased the expression of sirtuin1 and peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1)- α, which are involved in muscle synthesis. These findings suggest that the oral administration of NE suppresses skeletal muscle aging. Moreover, NE administration suppressed skin aging, including a decline in water content. Interestingly, oral administration of NE significantly extended the lifespan of SAMP8 mice, suggesting that its effectiveness as an anti-aging agent of various tissues including skeletal muscle, skin, and adipose tissue.
    Keywords:  lifespan extension; nacre extract; sarcopenia; skeletal muscle aging; skin aging
    DOI:  https://doi.org/10.3390/ph17060713
  4. Antioxidants (Basel). 2024 May 21. pii: 628. [Epub ahead of print]13(6):
    SVHRSP Alleviates Age-Related Cognitive Deficiency by Reducing Oxidative Stress and Neuroinflammation.
    Yingzi Wang, Zhenhua Wang, Songyu Guo, Qifa Li, Yue Kong, Aoran Sui, Jianmei Ma, Li Lu, Jie Zhao, Shao Li.
      BACKGROUND: Our previous studies have shown that scorpion venom heat-resistant synthesized peptide (SVHRSP) induces a significant extension in lifespan and improvements in age-related physiological functions in worms. However, the mechanism underlying the potential anti-aging effects of SVHRSP in mammals remains elusive.METHODS: Following SVHRSP treatment in senescence-accelerated mouse resistant 1 (SAMR1) or senescence-accelerated mouse prone 8 (SAMP8) mice, behavioral tests were conducted and brain tissues were collected for morphological analysis, electrophysiology experiments, flow cytometry, and protein or gene expression. The human neuroblastoma cell line (SH-SY5Y) was subjected to H2O2 treatment in cell experiments, aiming to establish a cytotoxic model that mimics cellular senescence. This model was utilized to investigate the regulatory mechanisms underlying oxidative stress and neuroinflammation associated with age-related cognitive impairment mediated by SVHRSP.
    RESULTS: SVHRSP significantly ameliorated age-related cognitive decline, enhanced long-term potentiation, restored synaptic loss, and upregulated the expression of synaptic proteins, therefore indicating an improvement in synaptic plasticity. Moreover, SVHRSP demonstrated a decline in senescent markers, including SA-β-gal enzyme activity, P16, P21, SIRT1, and cell cycle arrest. The underlying mechanisms involve an upregulation of antioxidant enzyme activity and a reduction in oxidative stress-induced damage. Furthermore, SVHRSP regulated the nucleoplasmic distribution of NRF2 through the SIRT1-P53 pathway. Further investigation indicated a reduction in the expression of proinflammatory factors in the brain after SVHRSP treatment. SVHRSP attenuated neuroinflammation by regulating the NF-κB nucleoplasmic distribution and inhibiting microglial and astrocytic activation through the SIRT1-NF-κB pathway. Additionally, SVHRSP significantly augmented Nissl body count while suppressing neuronal loss.
    CONCLUSION: SVHRSP could remarkably improve cognitive deficiency by inhibiting oxidative stress and neuroinflammation, thus representing an effective strategy to improve brain health.
    Keywords:  SVHRSP; Sirt 1 pathway; cognitive deficiency; neuroinflammation; oxidative stress
    DOI:  https://doi.org/10.3390/antiox13060628
  5. Sheng Li Xue Bao. 2024 Jun 25. 76(3): 418-428
    [Transition metal accumulation and cellular senescence].
    An-Na Xie, Guo-Yi Liu, Sun-Zhengyuan Zhang, Wei-Wei Dai.
      Aging refers to a progressive decline in biological functions, leading to age-related diseases and mortality. The transition metals, including iron, copper, and manganese, play important roles in human physiological and pathological processes. Substantial research has demonstrated that senescent cells accumulate higher levels of transition metals, which in turn accelerates the process of cellular senescence and related diseases through mechanisms such as production of excessive reactive oxygen species (ROS), induction of oxidative stress, DNA damage, and mitochondrial dysfunction. This review article provides a comprehensive overview of the causes of transition metal accumulation in senescent cells, as well as the mechanisms by which it further promotes cellular senescence and related diseases. The aim is to provide insights into anti-aging and treatment of aging-related diseases caused by transition metal accumulation.
  6. Aging (Albany NY). 2024 Jun 26. 16
    Senescent cell-derived vaccines: a new concept towards an immune response against cancer and aging?
    João Pessoa, Sandrina Nóbrega-Pereira, Bruno Bernardes de Jesus.
      Two recent seminal works have untangled the intricate role of tumor-associated senescent cells in cancer progression, or regression, by guiding our immune system against cancer cells. The characterization of these unique, yet diverse cell populations, should be considered, particularly when contemplating the use of senolytics, which are drugs that selectively eliminate senescent cells, in a cancer framework. Here, we will describe the current knowledge in this field. In particular, we will discuss how the presence of senescent cells in tumors could be used as a therapeutic target in immunogenic cancers and how we may hypothetically design an adaptive anti-aging vaccine.
    Keywords:  antigen; cancer; immunotherapy; senescence; tumor-associated senescent cells; vaccine
    DOI:  https://doi.org/10.18632/aging.205975
  7. Cell. 2024 Jun 21. pii: S0092-8674(24)00592-0. [Epub ahead of print]
    TERT activation targets DNA methylation and multiple aging hallmarks.
    Hong Seok Shim, Jonathan Iaconelli, Xiaoying Shang, Jiexi Li, Zheng D Lan, Shan Jiang, Kayla Nutsch, Brittney A Beyer, Luke L Lairson, Adam T Boutin, Michael J Bollong, Peter G Schultz, Ronald A DePinho.
      Insufficient telomerase activity, stemming from low telomerase reverse transcriptase (TERT) gene transcription, contributes to telomere dysfunction and aging pathologies. Besides its traditional function in telomere synthesis, TERT acts as a transcriptional co-regulator of genes pivotal in aging and age-associated diseases. Here, we report the identification of a TERT activator compound (TAC) that upregulates TERT transcription via the MEK/ERK/AP-1 cascade. In primary human cells and naturally aged mice, TAC-induced elevation of TERT levels promotes telomere synthesis, blunts tissue aging hallmarks with reduced cellular senescence and inflammatory cytokines, and silences p16INK4a expression via upregulation of DNMT3B-mediated promoter hypermethylation. In the brain, TAC alleviates neuroinflammation, increases neurotrophic factors, stimulates adult neurogenesis, and preserves cognitive function without evident toxicity, including cancer risk. Together, these findings underscore TERT's critical role in aging processes and provide preclinical proof of concept for physiological TERT activation as a strategy to mitigate multiple aging hallmarks and associated pathologies.
    Keywords:  adult neurogenesis; cognition; epigenetics; inflammation; p16(INK4a); senescence; telomerase; telomere
    DOI:  https://doi.org/10.1016/j.cell.2024.05.048
  8. Immun Ageing. 2024 Jun 26. 21(1): 43
    Adoptive NK cell therapy: a potential revolutionary approach in longevity therapeutics.
    Xuewen Deng, Hiroshi Terunuma.
      The aging process intricately involves immune system dynamics, with a crucial role in managing senescent cells (SNCs) and their senescence-associated secretory phenotypes (SASPs). Unfortunately, immunosenescence, a progressively dysregulated immunity with age, hampers effective SNC elimination, leading to accumulation, coupled with the release of SASPs, which, in turn, inhibits immunity and heightened susceptibility to aging-associated diseases (AADs). Natural killer (NK) cells, integral to the innate immune system, play a pivotal role in addressing SNCs swiftly. These cells also coordinate with other components of both innate and adaptive immunity to surveil and eliminate these cells. Accordingly, preserving NK cell function during aging is crucial for evading AADs and promoting healthy aging. Alternatively, NK-cell-based therapies present promising avenues for addressing the challenges associated with aging. Notable, recent studies in adoptive NK cell therapy have shown promise in rejuvenating immunosenescence, eliminating SNCs, and alleviating SASPs. This progress provides the proof-concept of adoptive NK cell therapy for senotherapy and holds promise as an emerging revolution in longevity therapeutics.
    Keywords:  Aging-associated diseases (AADs); Immunosenescence; NK cell therapy; Senescent cells (SNCs)
    DOI:  https://doi.org/10.1186/s12979-024-00451-2
  9. Cell Death Dis. 2024 Jun 24. 15(6): 443
    Aging and homeostasis of the hypodermis in the age-related deterioration of skin function.
    Meiqi Liu, Feng Lu, Jingwei Feng.
      Adipose tissues in the hypodermis, the crucial stem cell reservoir in the skin and the endocrine organ for the maintenance of skin homeostasis undergo significant changes during skin aging. Dermal white adipose tissue (dWAT) has recently been recognized as an important organ for both non-metabolic and metabolic health in skin regeneration and rejuvenation. Defective differentiation, adipogenesis, improper adipocytokine production, and immunological dissonance dysfunction in dWAT lead to age-associated clinical changes. Here, we review age-related alterations in dWAT across levels, emphasizing the mechanisms underlying the regulation of aging. We also discuss the pathogenic changes involved in age-related fat dysfunction and the unfavorable consequences of accelerated skin aging, such as chronic inflammaging, immunosenescence, delayed wound healing, and fibrosis. Research has shown that adipose aging is an early initiation event and a potential target for extending longevity. We believe that adipose tissues play an essential role in aging and form a potential therapeutic target for the treatment of age-related skin diseases. Further research is needed to improve our understanding of this phenomenon.
    DOI:  https://doi.org/10.1038/s41419-024-06818-z
  10. Aging Dis. 2024 06 14.
    Human Aging and Age-Related Diseases: From Underlying Mechanisms to Pro-Longevity Interventions.
    Piotr Pawel Chmielewski, Krzysztof Data, Bartłomiej Strzelec, Maryam Farzaneh, Amir Anbiyaiee, Uzma Zaheer, Shahab Uddin, Mohadeseh Sheykhi-Sabzehpoush, Paul Mozdziak, Maciej Zabel, Piotr Dzięgiel, Bartosz Kempisty.
      As human life expectancy continues to rise, becoming a pressing global concern, it brings into focus the underlying mechanisms of aging. The increasing lifespan has led to a growing elderly population grappling with age-related diseases (ARDs), which strains healthcare systems and economies worldwide. While human senescence was once regarded as an immutable and inexorable phenomenon, impervious to interventions, the emerging field of geroscience now offers innovative approaches to aging, holding the promise of extending the period of healthspan in humans. Understanding the intricate links between aging and pathologies is essential in addressing the challenges presented by aging populations. A substantial body of evidence indicates shared mechanisms and pathways contributing to the development and progression of various ARDs. Consequently, novel interventions targeting the intrinsic mechanisms of aging have the potential to delay the onset of diverse pathological conditions, thereby extending healthspan. In this narrative review, we discuss the most promising methods and interventions aimed at modulating aging, which harbor the potential to mitigate ARDs in the future. We also outline the complexity of senescence and review recent empirical evidence to identify rational strategies for promoting healthy aging.
    DOI:  https://doi.org/10.14336/AD.2024.0280
  11. Nat Prod Res. 2024 Jun 28. 1-6
    The anti-aging effects of Chlorella polysaccharide extract in Caenorhabditis elegans.
    Shu-Ting Feng, Chang-Tai You, Zi-Kang Pan, Wen-Yi Gao, Ding-Ding Wang, Li-Li Hu.
      Chlorella has a variety of biological activities, and it is worth further exploring its pharmacological effects. In this study, we investigated the antioxidant and anti-ageing activities of Chlorella polysaccharide extract (CPE). Further studies revealed that CPE exhibited anti-ageing, and antioxidant activities in vivo, including an extended Caenorhabditis elegans stress resistance, decreased deposition of lipofuscin, and reduced effects of amyloid β protein on mobility, decreased levels of reactive oxygen species and increased activity of antioxidant enzymes. Moreover, it dramatically increased the expression of anti-stress and longevity genes and reduced the expression of ageing-related genes; therefore, it was hypothesised that the mechanism of the age-delaying effect of CPE was related to the insulin signalling pathway. In summary, CPE could delay ageing and provide a new avenue for the application and development of CPE.
    Keywords:  Caenorhabditis elegans; Chlorella polysaccharide extract; anti-aging; insulin/IGF-1 signalling
    DOI:  https://doi.org/10.1080/14786419.2024.2371562
  12. Adv Biol (Weinh). 2024 Jun 27. e2400079
    Biomarkers of Cellular Senescence and Aging: Current State-of-the-Art, Challenges and Future Perspectives.
    Subramanian Muthamil, Hyun-Yong Kim, Hyun-Jun Jang, Ji-Hyo Lyu, Ung Cheol Shin, Younghoon Go, Seong-Hoon Park, Hee Gu Lee, Jun Hong Park.
      Population aging has increased the global prevalence of aging-related diseases, including cancer, sarcopenia, neurological disease, arthritis, and heart disease. Understanding aging, a fundamental biological process, has led to breakthroughs in several fields. Cellular senescence, evinced by flattened cell bodies, vacuole formation, and cytoplasmic granules, ubiquitously plays crucial roles in tissue remodeling, embryogenesis, and wound repair as well as in cancer therapy and aging. The lack of universal biomarkers for detecting and quantifying senescent cells, in vitro and in vivo, constitutes a major limitation. The applications and limitations of major senescence biomarkers, including senescence-associated β-galactosidase staining, telomere shortening, cell-cycle arrest, DNA methylation, and senescence-associated secreted phenotypes are discussed. Furthermore, explore senotherapeutic approaches for aging-associated diseases and cancer. In addition to the conventional biomarkers, this review highlighted the in vitro, in vivo, and disease models used for aging studies. Further, technologies from the current decade including multi-omics and computational methods used in the fields of senescence and aging are also discussed in this review. Understanding aging-associated biological processes by using cellular senescence biomarkers can enable therapeutic innovation and interventions to improve the quality of life of older adults.
    Keywords:  SASPs; SA‐β‐gal; aging; multi‐omics; organoids; senescence; senotherapeutics
    DOI:  https://doi.org/10.1002/adbi.202400079
  13. Int J Mol Sci. 2024 Jun 07. pii: 6332. [Epub ahead of print]25(12):
    Improvement in Epigenetic Aging Clock Induced by BioBran Containing Rice Kefiran in Relation to Various Biomarkers: A Pilot Study.
    Satoshi Kawakami, Ryo Ninomiya, Yusuke Maeda.
      Many lifestyle-related diseases such as cancer, dementia, myocardial infarction, and stroke are known to be caused by aging, and the WHO's ICD-11 (International Classification of Diseases, 11th edition) created the code "aging-related" in 2022. In other words, aging is irreversible but aging-related diseases are reversible, so taking measures to treat them is important for health longevity and preventing other diseases. Therefore, in this study, we used BioBran containing rice kefiran as an approach to improve aging. Rice kefiran has been reported to improve the intestinal microflora, regulate the intestines, and have anti-aging effects. BioBran has also been reported to have antioxidant effects and improve liver function, and human studies have shown that it affects the diversity of the intestinal microbiota. Quantitative measures of aging that correlate with disease risk are now available through the epigenetic clock test, which examines the entire gene sequence and determines biological age based on the methylation level. Horvath's Clock is the best known of many epigenetic clock tests and was published by Steve Horvath in 2013. In this study, we examine the effect of using Horvath's Clock to improve aging and report on the results, which show a certain effect.
    Keywords:  BioBran; aging; epigenetic aging clock; lifestyle; nutrition; rice kefiran
    DOI:  https://doi.org/10.3390/ijms25126332
  14. Nutrients. 2024 Jun 17. pii: 1907. [Epub ahead of print]16(12):
    Exogenous Nucleotides Improve the Skin Aging of SAMP8 Mice by Modulating Autophagy through MAPKs and AMPK Pathways.
    Rui Fan, Ying Zhang, Rui Liu, Chan Wei, Xiujuan Wang, Xin Wu, Xiaochen Yu, Zhen Li, Ruixue Mao, Jiani Hu, Na Zhu, Xinran Liu, Yong Li, Meihong Xu.
      The skin, serving as the body's primary defense against external elements, plays a crucial role in protecting the body from infections and injuries, as well as maintaining overall homeostasis. Skin aging, a common manifestation of the aging process, involves the gradual deterioration of its normal structure and repair mechanisms. Addressing the issue of skin aging is increasingly imperative. Multiple pieces of evidence indicate the potential anti-aging effects of exogenous nucleotides (NTs) through their ability to inhibit oxidative stress and inflammation. This study aims to investigate whether exogenous NTs can slow down skin aging and elucidate the underlying mechanisms. To achieve this objective, senescence-accelerated mouse prone-8 (SAMP8) mice were utilized and randomly allocated into Aging, NTs-low, NTs-middle, and NTs-high groups, while senescence-accelerated mouse resistant 1 (SAMR1) mice were employed as the control group. After 9 months of NT intervention, dorsal skin samples were collected to analyze the pathology and assess the presence and expression of substances related to the aging process. The findings indicated that a high-dose NT treatment led to a significant increase in the thickness of the epithelium and dermal layers, as well as Hyp content (p < 0.05). Additionally, it was observed that low-dose NT intervention resulted in improved aging, as evidenced by a significant decrease in p16 expression (p < 0.05). Importantly, the administration of high doses of NTs could improve, in some ways, mitochondrial function, which is known to reduce oxidative stress and promote ATP and NAD+ production significantly. These observed effects may be linked to NT-induced autophagy, as evidenced by the decreased expression of p62 and increased expression of LC3BI/II in the intervention groups. Furthermore, NTs were found to upregulate pAMPK and PGC-1α expression while inhibiting the phosphorylation of p38MAPK, JNK, and ERK, suggesting that autophagy may be regulated through the AMPK and MAPK pathways. Therefore, the potential induction of autophagy by NTs may offer benefits in addressing skin aging through the activation of the AMPK pathway and the inhibition of the MAPK pathway.
    Keywords:  AMPK pathway; MAPK pathway; SAMP8 mice; autophagy; exogenous nucleotides; skin aging
    DOI:  https://doi.org/10.3390/nu16121907
  15. Tissue Eng Regen Med. 2024 Jun 24.
    Adipose-Derived Mesenchymal Stem Cells and Their Derived Epidermal Progenitor Cells Conditioned Media Ameliorate Skin Aging in Rats.
    Omar I Badr, Aya Anter, Ihab Magdy, Marvellous Chukueggu, Moamen Khorshid, Mohamed Darwish, Mohamed Farrag, Menna Elsayed, Youmna Amr, Yomna Amgad, Tasnim Mahmoud, Mohamed M Kamal.
      BACKGROUND: Skin alterations are among the most prominent signs of aging, and they arise from both intrinsic and extrinsic factors that interact and mutually influence one another. The use of D-galactose as an aging model in animals has been widely employed in anti-aging research. Adipose tissue-derived mesenchymal stem cells (Ad-MSCs) are particularly promising for skin anti-aging therapy due to their capacity for effective re-epithelization and secretion of various growth factors essential for skin regeneration. Accordingly, we aimed to examine the potential utility of Ad-MSCs as a therapy for skin anti-aging.METHODS: In this study, we isolated and characterized adipose-derived mesenchymal stem cells (Ad-MSCs) from the epididymal fat of male Sprague Dawley rats. We assessed the in vitro differentiation of Ad-MSCs into epidermal progenitor cells (EPCs) using ascorbic acid and hydrocoritsone. Additionally, we induced skin aging in female Sprague Dawley rats via daily intradermal injection of D-galactose over a period of 8 weeks. Then we evaluated the therapeutic potential of intradermal transplantation of Ad-MSCs and conditioned media (CM) derived from differentiated EPCs in the D-galactose-induced aging rats. Morphological assessments, antioxidant assays, and histopathological examinations were performed to investigate the effects of the treatments.
    RESULTS: Our findings revealed the significant capability of Ad-MSCs to differentiate into EPCs. Notably, compared to the group that received CM treatment, the Ad-MSCs-treated group exhibited a marked improvement in morphological appearance, antioxidant levels and histological features.
    CONCLUSIONS: These results underscore the effectiveness of Ad-MSCs in restoring skin aging as a potential therapy for skin aging.
    Keywords:   d-galactose; Adipose tissue; Epidermal progenitor cells; Mesenchymal stem cells; Regenerative medicine; Skin aging
    DOI:  https://doi.org/10.1007/s13770-024-00643-3
  16. J Mol Biol. 2024 Jun 20. pii: S0022-2836(24)00267-5. [Epub ahead of print] 168672
    HUMAN CST STIMULATES BASE EXCISION REPAIR TO PREVENT THE ACCUMULATION OF OXIDATIVE DNA DAMAGE.
    Brandon C Wysong, P Logan Schuck, Madhumita Sridharan, Sophie Carrison, Yuichihiro Murakami, Lata Balakrishnan, Jason A Stewart.
      CTC1-STN1-TEN1 (CST) is a single-stranded DNA binding protein vital for telomere length maintenance with additional genome-wide roles in DNA replication and repair. While CST was previously shown to function in double-strand break repair and promote replication restart, it is currently unclear whether it has specialized roles in other DNA repair pathways. Proper and efficient repair of DNA is critical to protecting genome integrity. Telomeres and other G-rich regions are strongly predisposed to oxidative DNA damage in the form of 8-oxoguanines, which are typically repaired by the base-excision repair (BER) pathway. Moreover, recent studies suggest that CST functions in the repair of oxidative DNA lesions. Therefore, we tested whether CST interacts with and regulates BER protein activity. Here, we show that CST robustly stimulates proteins involved in BER, including OGG1, Pol β, APE1, and LIGI, on both telomeric and non-telomeric DNA substrates. Biochemical reconstitution of the pathway indicates that CST stimulates BER. Finally, knockout of STN1 or CTC1 leads to increased levels of 8-oxoguanine, suggesting defective BER in the absence of CST. Combined, our results define an undiscovered function of CST in BER, where it acts as a stimulatory factor to promote efficient genome-wide oxidative repair.
    Keywords:  CST complex; DNA repair; base excision repair (BER); oxidative damage
    DOI:  https://doi.org/10.1016/j.jmb.2024.168672
  17. Int J Mol Sci. 2024 Jun 15. pii: 6591. [Epub ahead of print]25(12):
    Involvement of Matricellular Proteins in Cellular Senescence: Potential Therapeutic Targets for Age-Related Diseases.
    Motomichi Fujita, Manabu Sasada, Takuya Iyoda, Fumio Fukai.
      Senescence is a physiological and pathological cellular program triggered by various types of cellular stress. Senescent cells exhibit multiple characteristic changes. Among them, the characteristic flattened and enlarged morphology exhibited in senescent cells is observed regardless of the stimuli causing the senescence. Several studies have provided important insights into pro-adhesive properties of cellular senescence, suggesting that cell adhesion to the extracellular matrix (ECM), which is involved in characteristic morphological changes, may play pivotal roles in cellular senescence. Matricellular proteins, a group of structurally unrelated ECM molecules that are secreted into the extracellular environment, have the unique ability to control cell adhesion to the ECM by binding to cell adhesion receptors, including integrins. Recent reports have certified that matricellular proteins are closely involved in cellular senescence. Through this biological function, matricellular proteins are thought to play important roles in the pathogenesis of age-related diseases, including fibrosis, osteoarthritis, intervertebral disc degeneration, atherosclerosis, and cancer. This review outlines recent studies on the role of matricellular proteins in inducing cellular senescence. We highlight the role of integrin-mediated signaling in inducing cellular senescence and provide new therapeutic options for age-related diseases targeting matricellular proteins and integrins.
    Keywords:  PAI-1; communication network factor; matricryptic site; matricryptins; osteopontin; periostin; senescence-associated secretory phenotype; senomorphic drug; senotherapy; tenascin-C
    DOI:  https://doi.org/10.3390/ijms25126591
  18. bioRxiv. 2024 Jun 12. pii: 2024.06.12.598646. [Epub ahead of print]
    A mechanism for telomere-specific telomere length regulation.
    Gabriela M Teplitz, Emeline Pasquier, Erin Bonnell, Evelina De Laurentiis, Louise Bartle, Jean-François Lucier, Samantha Sholes, Carol W Greider, Raymund J Wellinger.
      Telomeric DNA, composed of short, direct repeats, is of crucial importance for chromosome stability. Due to intrinsic problems with replicating this DNA, the repeat tracts shorten at each cell division. Once repeat tracts become critically short, a telomeric stress signal induces cellular senescence and division arrest, which eventually may lead to devastating age-related degenerative diseases associated with dysfunctional telomers. Conversely, maintenance of telomere length by telomerase upregulation is a hallmark of cancer. Therefore, telomere length is a critical determinant of telomere function. How telomere length is established and molecular mechanisms for telomere-specific length regulation remained unknown. Here we show that subtelomeric chromatin is a determinant for how telomere equilibrium set-length is established in cis . The results demonstrate that telomerase recruitment mediated by the telomere-associated Sir4 protein is modulated on chromosome 3L in a telomere-specific way. Increased Sir4 abundance on subtelomeric heterochromatin of this specific telomere leads to telomere lengthening of only that telomere in cis , but not at other telomeres. Therefore, this work describes a mechanism for a how telomere-specific repeat tract length can be established. Further, our results will force the evaluation of telomere length away from a generalized view to a more telomere-specific consideration.
    DOI:  https://doi.org/10.1101/2024.06.12.598646
  19. Int J Mol Sci. 2024 Jun 20. pii: 6793. [Epub ahead of print]25(12):
    Towards Healthy Longevity: Comprehensive Insights from Molecular Targets and Biomarkers to Biological Clocks.
    Khalishah Yusri, Sanjay Kumar, Sheng Fong, Jan Gruber, Vincenzo Sorrentino.
      Aging is a complex and time-dependent decline in physiological function that affects most organisms, leading to increased risk of age-related diseases. Investigating the molecular underpinnings of aging is crucial to identify geroprotectors, precisely quantify biological age, and propose healthy longevity approaches. This review explores pathways that are currently being investigated as intervention targets and aging biomarkers spanning molecular, cellular, and systemic dimensions. Interventions that target these hallmarks may ameliorate the aging process, with some progressing to clinical trials. Biomarkers of these hallmarks are used to estimate biological aging and risk of aging-associated disease. Utilizing aging biomarkers, biological aging clocks can be constructed that predict a state of abnormal aging, age-related diseases, and increased mortality. Biological age estimation can therefore provide the basis for a fine-grained risk stratification by predicting all-cause mortality well ahead of the onset of specific diseases, thus offering a window for intervention. Yet, despite technological advancements, challenges persist due to individual variability and the dynamic nature of these biomarkers. Addressing this requires longitudinal studies for robust biomarker identification. Overall, utilizing the hallmarks of aging to discover new drug targets and develop new biomarkers opens new frontiers in medicine. Prospects involve multi-omics integration, machine learning, and personalized approaches for targeted interventions, promising a healthier aging population.
    Keywords:  aging; biological clocks; biomarkers; clinical trials; drug development; geroprotector; healthy longevity; machine learning; omics; supplements
    DOI:  https://doi.org/10.3390/ijms25126793
  20. RNA. 2024 Jun 25. pii: rna.080043.124. [Epub ahead of print]
    Small molecule telomerase inhibitors are also potent inhibitors of telomeric C-strand synthesis.
    Kaitlin Johnson, Julia M Seidel, Thomas R Cech.
      Telomere replication is essential for continued proliferation of human cells, such as stem cells and cancer cells. Telomerase lengthens the telomeric G-strand, while C-strand replication is accomplished by CST-polymerase α -primase (CST-PP). Replication of both strands is inhibited by formation of G-quadruplex (GQ) structures in the G-rich single-stranded DNA. TMPyP4 and pyridostatin (PDS), which stabilize GQ structures in both DNA and RNA, inhibit telomerase in vitro, and they cause telomere shortening in human cells that has been attributed to telomerase inhibition. Here, we show that TMPyP4 and PDS also inhibit C-strand synthesis by stabilizing DNA secondary structures and thereby preventing CST-PP from binding to telomeric DNA. We also show that these small molecules inhibit CST-PP binding to a DNA sequence containing no consecutive guanine residues, which is unlikely to form GQs. Thus, while these "telomerase inhibitors" indeed inhibit telomerase, they are also robust inhibitors of telomeric C-strand synthesis. Furthermore, given their limited specificity for GQ structures, they may disrupt many other protein-nucleic acid interactions in human cells.
    Keywords:  G-quadruplex; GQ stabilizers; Pyridostatin; TMPyP4; Telomere replication
    DOI:  https://doi.org/10.1261/rna.080043.124
  21. Genes (Basel). 2024 May 22. pii: 659. [Epub ahead of print]15(6):
    Lack of T04C9.1, the Homologue of Mammalian APPL2, Leads to Premature Ageing and Shortens Lifespan in Caenorhabditis elegans.
    Zirui Li, Zhiqiang Chen, Lianghao Zhao, Jiaqi Sun, Lin Yin, Yuwei Jiang, Xiaotong Shi, Ziye Song, Lu Zhang.
      Ageing has been identified as an independent risk factor for various diseases; however, the physiological basis and molecular changes related to ageing are still largely unknown. Here, we show that the level of APPL2, an adaptor protein, is significantly reduced in the major organs of aged mice. Knocking down APPL2 causes premature ageing of human umbilical vein endothelial cells (HUVECs). We find that a lack of T04C9.1, the homologue of mammalian APPL2, leads to premature ageing, slow movements, lipid deposition, decreased resistance to stresses, and shortened lifespan in Caenorhabditis elegans (C. elegans), which are associated with decreased autophagy. Activating autophagy by rapamycin or inhibition of let-363 suppresses the age-related alternations, impaired motility, and shortened lifespan of C. elegans, which are reversed by knocking down autophagy-related genes. Our work provides evidence that APPL2 and its C. elegans homologue T04C9.1 decrease with age and reveals that a lack of T04C9.1 bridges autophagy decline and ageing in C. elegans.
    Keywords:  APPL2; C. elegans; T04C9.1; ageing; autophagy; lifespan
    DOI:  https://doi.org/10.3390/genes15060659
  22. Cell Death Discov. 2024 Jun 22. 10(1): 296
    DNA methylation as an epigenetic mechanism in the regulation of LEDGF expression and biological response in aging and oxidative stress.
    Biju Bhargavan, Bhavana Chhunchha, Eri Kubo, Dhirendra P Singh.
      The physiological quantum of stress-inducible transcriptional protein, Lens Epithelium-Derived Growth Factor (LEDGF), is vital for the maintenance of cellular physiology. Erratic epigenetic reprogramming in response to oxidative stress or with advancing age is found to be a major cause in the gene silencing, leading to pathobiologies. Using aging human (h) eye lens/lens epithelial cells (LECs) coupled with redox-active Peroxiredoxin 6 (Prdx6)-deficient (Prdx6-/-) mLECs as model systems, herein, we showed that in aging/oxidative stress, the human LEDGF gene was regulated by unique methylation patterns of CGs nucleotides within and around the Sp1 binding site(s) of CpG island of the LEDGF promoter (-170 to -27nts). The process caused the repression of LEDGF and its target, Hsp27, resulting in reactive oxygen species (ROS) amplification and cellular insults. This phenomenon was opposed to the unmethylated promoter in LECs. Clinically, we observed that the loss of LEDGF in the Prdx6-/- mLECs or aging lenses/LECs, correlating with increased expression of DNMT1, DNMT3a, and DNMT3b along with the methyl CpG binding protein 2 (MeCP2). Upon oxidative stress, the expression of these molecules was increased with the dramatic reduction in LEDGF expression. While demethylating agent, 5-Aza deoxycytidine (5-AzaC) transposed the aberrant methylation status, and revived LEDGF and Hsp27 expression. Mechanistically, the chloramphenicol acetyltransferase (CAT) reporter gene driven by the LEDGF promoter (-170/ + 35) and ChIP assays uncovered that 5-AzaC acted on GC/Sp1 sites to release LEDGF transcription. The data argued, for the first time, that de novo methylation of CGs around and within Sp1 sites of the CpG island directly disrupted Sp1 activity, which ensued in LEDGF repression and its biological functions. The findings should improve our understanding of cellular insults-associated with aberrant DNMTs-mediated LEDGF's activity, and can offer strategies for therapeutic intervention to halt aging/oxidative stress-induced abnormalities.
    DOI:  https://doi.org/10.1038/s41420-024-02076-2
  23. Ibrain. 2024 ;10(2): 225-230
    Endothelial cellular senescence and tau accumulation: An interplay full of opportunities?
    Doriana Oliveri, Giorgia Moschetti, Anna Griego, Edoardo Scarpa.
      Recent research has shown that tau protein can be passed to neighboring cells, leading to cellular senescence in the endothelial cells present in the central nervous system (CNS). This discovery could potentially open new doors for testing novel therapeutic compounds that specifically target senescent cells (senolytics) or for identifying new biomarkers that can enable early detection of tauopathies and dementia.
    Keywords:  brain; cellular senescence; tauopathies
    DOI:  https://doi.org/10.1002/ibra.12154
  24. Bioengineering (Basel). 2024 May 21. pii: 524. [Epub ahead of print]11(6):
    Role of Mesenchymal Stem/Stromal Cells (MSCs) and MSC-Derived Extracellular Vesicles (EVs) in Prevention of Telomere Length Shortening, Cellular Senescence, and Accelerated Biological Aging.
    Myrna Y Gonzalez Arellano, Matthew VanHeest, Sravya Emmadi, Amal Abdul-Hafez, Sherif Abdelfattah Ibrahim, Ranga P Thiruvenkataramani, Rasha S Teleb, Hady Omar, Tulasi Kesaraju, Tarek Mohamed, Burra V Madhukar, Said A Omar.
      Biological aging is defined as a progressive decline in tissue function that eventually results in cell death. Accelerated biologic aging results when the telomere length is shortened prematurely secondary to damage from biological or environmental stressors, leading to a defective reparative mechanism. Stem cells therapy may have a potential role in influencing (counteract/ameliorate) biological aging and maintaining the function of the organism. Mesenchymal stem cells, also called mesenchymal stromal cells (MSCs) are multipotent stem cells of mesodermal origin that can differentiate into other types of cells, such as adipocytes, chondrocytes, and osteocytes. MSCs influence resident cells through the secretion of paracrine bioactive components such as cytokines and extracellular vesicles (EVs). This review examines the changes in telomere length, cellular senescence, and normal biological age, as well as the factors contributing to telomere shortening and accelerated biological aging. The role of MSCs-especially those derived from gestational tissues-in prevention of telomere shortening (TS) and accelerated biological aging is explored. In addition, the strategies to prevent MSC senescence and improve the antiaging therapeutic application of MSCs and MSC-derived EVs in influencing telomere length and cellular senescence are reviewed.
    Keywords:  biological age; exosomes; extracellular vesicles; mesenchymal stem cells; telomere length
    DOI:  https://doi.org/10.3390/bioengineering11060524
  25. Antioxidants (Basel). 2024 Jun 03. pii: 686. [Epub ahead of print]13(6):
    Artesunate Exerts Organ- and Tissue-Protective Effects by Regulating Oxidative Stress, Inflammation, Autophagy, Apoptosis, and Fibrosis: A Review of Evidence and Mechanisms.
    Mingtao Zhu, Yu Wang, Jianwei Han, Yanping Sun, Shuang Wang, Bingyou Yang, Qiuhong Wang, Haixue Kuang.
      The human body comprises numerous organs and tissues operating in synchrony, it facilitates metabolism, circulation, and overall organismal function. Consequently, the well-being of our organs and tissues significantly influences our overall health. In recent years, research on the protective effects of artesunate (AS) on various organ functions, including the heart, liver, brain, lungs, kidneys, gastrointestinal tract, bones, and others has witnessed significant advancements. Findings from in vivo and in vitro studies suggest that AS may emerge as a newfound guardian against organ damage. Its protective mechanisms primarily entail the inhibition of inflammatory factors and affect anti-fibrotic, anti-aging, immune-enhancing, modulation of stem cells, apoptosis, metabolic homeostasis, and autophagy properties. Moreover, AS is attracting a high level of interest because of its obvious antioxidant activities, including the activation of Nrf2 and HO-1 signaling pathways, inhibiting the release of reactive oxygen species, and interfering with the expression of genes and proteins associated with oxidative stress. This review comprehensively outlines the recent strides made by AS in alleviating organismal injuries stemming from various causes and protecting organs, aiming to serve as a reference for further in-depth research and utilization of AS.
    Keywords:  antioxidant properties; artesunate; fibrosis; inflammation; molecular mechanisms; organ protection
    DOI:  https://doi.org/10.3390/antiox13060686
  26. Cell Reprogram. 2024 Jun;26(3): 93-95
    Revitalizing the Aging Immune System Through Selective Stem Cell Targeting.
    Anna Konturek-Ciesla, David Bryder.
      The interplay between aging and immune system deterioration presents a formidable challenge to human health, especially in the context of a globally aging population. Aging is associated with a decline in the body's ability to combat infections and an increased risk of various diseases, underlining the importance of rejuvenating the immune system as a strategy for promoting healthier aging. In issue 628 of Nature (2024), Ross et al. present a compelling study that introduces a novel strategy for rejuvenating the aged immune system (Ross et al., 2024). By using antibodies to selectively eliminate "aberrant" hematopoietic stem cells (HSCs), this research opens new avenues for addressing age-related immune deterioration.
    DOI:  https://doi.org/10.1089/cell.2024.0029
  27. Mitochondrion. 2024 Jun 24. pii: S1567-7249(24)00081-3. [Epub ahead of print] 101923
    Role of mitochondrial homeostasis in D-galactose-induced cardiovascular ageing from bench to bedside.
    Yogita Sahu, Pratiksha Jamadade, Krushna Ch Maharana, Sanjiv Singh.
      Ageing is an inevitable phenomenon which affects the cellular to the organism level in the progression of the time. Oxidative stress and inflammation are now widely regarded as the key processes involved in the aging process, which may then cause significant harm to mitochondrial DNA, leading to apoptosis. Normal circulatory function is a significant predictor of disease-free life expectancy. Indeed, disorders affecting the cardiovascular system, which are becoming more common, are the primary cause of worldwide morbidity, disability, and mortality. Cardiovascular aging may precede or possibly underpin overall, age-related health decline. Numerous studies have foundmitochondrial mechanistc approachplays a vital role in the in the onset and development of aging. The D-galactose (D-gal)-induced aging model is well recognized and commonly used in the aging study. In this review we redeposit the association of the previous and current studies on mitochondrial homeostasis and its underlying mechanisms in D-galactose cardiovascular ageing. Further we focus the novel and the treatment strategies to combat the major complication leading to the cardiovascular ageing.
    Keywords:  Cardiovascular ageing; D-galactose; Mitochondrial Dynamics; Mitochondrial Homeostasis; Mitophagy
    DOI:  https://doi.org/10.1016/j.mito.2024.101923
  28. Ageing Res Rev. 2024 Jun 22. pii: S1568-1637(24)00209-5. [Epub ahead of print] 102391
    Stem cell-derived extracellular vesicles as senotherapeutics.
    Ekaterina Rudnitsky, Alex Braiman, Marina Wolfson, Khachik K Muradian, Vera Gorbunova, Gadi Turgeman, Vadim E Fraifeld.
      Cellular senescence (CS) is recognized as one of the hallmarks of aging, and an important player in a variety of age-related pathologies. Accumulation of senescent cells can promote a pro-inflammatory and pro-cancerogenic microenvironment. Among potential senotherapeutics are extracellular vesicles (EVs) (40-1000nm), including exosomes (40-150nm), that play an important role in cell-cell communications. Here, we review the most recent studies on the impact of EVs derived from stem cells (MSCs, ESCs, iPSCs) as well as non-stem cells of various types on CS and discuss potential mechanisms responsible for the senotherapeutic effects of EVs. The analysis revealed that (i) EVs derived from stem cells, pluripotent (ESCs, iPSCs) or multipotent (MSCs of various origin), can mitigate the cellular senescence phenotype both in vitro and in vivo; (ii) this effect is presumably senomorphic; (iii) EVs display cross-species activity, without apparent immunogenic responses. In summary, stem cell-derived EVs appear to be promising senotherapeutics, with a feasible application in humans.
    Keywords:  ESC; MSC; cellular senescence; extracellular vesicles; iPSC
    DOI:  https://doi.org/10.1016/j.arr.2024.102391
  29. Med Sci Sports Exerc. 2024 Jun 27.
    The Influence of Aging on the Unfolded Protein Response in Human Skeletal Muscle at Rest and Following Acute Exercise.
    Kelly L Michie, Hawley E Kunz, Surendra Dasari, Ian R Lanza.
      BACKGROUND: The unfolded protein response (UPR) is a proteostatic process that is activated in response to endoplasmic reticulum stress. It is currently unclear how aging influences the chronic and adaptive UPR in human skeletal muscle. Here we determined the effect of aging on UPR activation at rest, in response to exercise, and the associations with muscle function.METHODS: Thirty young (20-35 yrs) and 50 older (65-85 yrs) individuals were enrolled. Vastus lateralis biopsies were performed at rest and 3 hrs and 48 hrs after a single bout of resistance exercise. The abundance of UPR-related transcripts and proteins were measured by RNA sequencing and Western blotting, respectively. Fractional synthetic rates (FSR) of muscle protein were determined by mass spectrometry following intravenous infusion of 13C6 phenylalanine.
    RESULTS: Older adults demonstrated elevated transcriptional and proteomic markers of UPR activation in resting muscle. Resting UPR gene expression was negatively associated with muscle strength and power in older adults. The UPR is similarly activated by acute resistance exercise in young and older adults and positively associated with muscle function but not the anabolic response to exercise.
    CONCLUSIONS: Skeletal muscle from older adults exhibits chronically activated UPR, which accompanies functional decline. The adaptive UPR is a proteostatic mechanism that is upregulated in response to exercise in young and older adults and positively associated with muscle function.
    DOI:  https://doi.org/10.1249/MSS.0000000000003508
  30. bioRxiv. 2024 Jun 13. pii: 2024.05.17.594584. [Epub ahead of print]
    fmo-4 promotes longevity and stress resistance via ER to mitochondria calcium regulation in C. elegans.
    A M Tuckowski, S Beydoun, E S Kitto, A Bhat, M B Howington, A Sridhar, M Bhandari, K Chambers, S F Leiser.
      Flavin-containing monooxygenases (FMOs) are a conserved family of xenobiotic enzymes upregulated in multiple longevity interventions, including nematode and mouse models. Previous work supports that C. elegans fmo-2 promotes longevity, stress resistance, and healthspan by rewiring endogenous metabolism. However, there are five C. elegans FMOs and five mammalian FMOs, and it is not known whether promoting longevity and health benefits is a conserved role of this gene family. Here, we report that expression of C. elegans fmo-4 promotes lifespan extension and paraquat stress resistance downstream of both dietary restriction and inhibition of mTOR. We find that overexpression of fmo-4 in just the hypodermis is sufficient for these benefits, and that this expression significantly modifies the transcriptome. By analyzing changes in gene expression, we find that genes related to calcium signaling are significantly altered downstream of fmo-4 expression. Highlighting the importance of calcium homeostasis in this pathway, fmo-4 overexpressing animals are sensitive to thapsigargin, an ER stressor that inhibits calcium flux from the cytosol to the ER lumen. This calcium/ fmo-4 interaction is solidified by data showing that modulating intracellular calcium with either small molecules or genetics can change expression of fmo-4 and/or interact with fmo-4 to affect lifespan and stress resistance. Further analysis supports a pathway where fmo-4 modulates calcium homeostasis downstream of activating transcription factor-6 ( atf-6 ), whose knockdown induces and requires fmo-4 expression. Together, our data identify fmo-4 as a longevity- promoting gene whose actions interact with known longevity pathways and calcium homeostasis.
    DOI:  https://doi.org/10.1101/2024.05.17.594584
  31. Aging Dis. 2024 May 21.
    m6A Reader HNRNPC Facilitates Adipogenesis by Regulating Cytoskeletal Remodeling through Enhanced Lcp1 mRNA Stability.
    Wenhua Xie, Yewei Cui, Lingzhi Yue, Ting Zhang, Chenglong Huang, Xinyu Yu, Dan Ma, Dongfang Liu, Rui Cheng, Xueya Zhao, Xi Li.
      Reduced adipogenesis is a prominent characteristic of aging adipose tissue and is closely tied to the development of metabolic disorders associated with aging. Epigenetic modification plays a crucial role in the aging process, yet the role of N6-methyladenosine (m6A), the most prevalent RNA modification, in regulating adipose tissue aging remains uncertain. Our study found that levels of m6A and its recognition protein, heterogeneous nuclear ribonucleoprotein C (HNRNPC), decrease in adipose tissue as individuals age. Lower levels of HNRNPC were also linked to reduced adipogenesis during aging. Through loss and gain of function experiments with HNRNPC, we established a positive correlation between HNRNPC and adipogenesis in vitro. Hnrnpc-APKO mice displayed decreased adipogenesis, increased insulin resistance, elevated expression of aging-related and inflammation-related genes, decreased lipogenesis-related genes, and other metabolic disorders compared to their littermates. Additionally, we discovered that HNRNPC facilitated the stability of lymphocyte cytosolic protein 1 (Lcp1) mRNA by binding to the m6A motif of LCP1. Overexpression of LCP1 mitigated the inhibition of adipogenesis caused by decreased HNRNPC through modulation of cytoskeletal remodeling. Finally, our findings demonstrate that anti-aging treatments could enhance HNRNPC levels. In conclusion, HNRNPC is positively associated with reduced adipogenesis during aging, and increacing HNRNPC levels through anti-aging treatments highlights its potential as a therapeutic target for addressing metabolic imbalances in adipose tissue related to aging.
    DOI:  https://doi.org/10.14336/AD.2024.0132
  32. J Cachexia Sarcopenia Muscle. 2024 Jun 26.
    Aerobic exercise suppresses CCN2 secretion from senescent muscle stem cells and boosts muscle regeneration in aged mice.
    Fan Li, Fulong Zhang, Haiwang Shi, Honglin Xia, Xiaobei Wei, Siqi Liu, Tao Wu, Yuecheng Li, Feng Shu, Mengjie Chen, Jie Li, Rui Duan.
      BACKGROUND: Aging negatively impacts tissue repair, particularly in skeletal muscle, where the regenerative capacity of muscle stem cells (MuSCs) diminishes with age. Although aerobic exercise is known to attenuate skeletal muscle atrophy, its specific impact on the regenerative and repair capacity of MuSCs remains unclear.METHODS: Mice underwent moderate-intensity continuous training (MICT) from 9 months (aged + Ex-9M) or 20 months (aged + Ex-20M) to 25 months, with age-matched (aged) and adult controls. Histological examinations and MuSC transplantation assays assessed aerobic exercise effects on MuSC function and muscle regeneration. CCN2/connective tissue growth factor modulation (overexpression and knockdown) in MuSCs and AICAR supplementation effects were explored.
    RESULTS: Aged mice displayed significantly reduced running duration (65.33 ± 4.32 vs. 161.9 ± 1.29 min, mean ± SD, P < 0.001) and distance (659.17 ± 103.64 vs. 3058.28 ± 46.26 m, P < 0.001) compared with adults. This reduction was accompanied by skeletal muscle weight loss and decreased myofiber cross-sectional area (CSA). However, MICT initiated at 9 or 20 months led to a marked increase in running duration (142.75 ± 3.14 and 133.86 ± 20.47 min, respectively, P < 0.001 compared with aged mice) and distance (2347.58 ± 145.11 and 2263 ± 643.87 m, respectively, P < 0.001). Additionally, MICT resulted in increased skeletal muscle weight and enhanced CSA. In a muscle injury model, aged mice exhibited fewer central nuclear fibres (CNFs; 266.35 ± 68.66/mm2), while adult, aged + Ex-9M and aged + Ex-20M groups showed significantly higher CNF counts (610.82 ± 46.76, 513.42 ± 47.19 and 548.29 ± 71.82/mm2, respectively; P < 0.001 compared with aged mice). MuSCs isolated from aged mice displayed increased CCN2 expression, which was effectively suppressed by MICT. Transplantation of MuSCs overexpressing CCN2 (Lenti-CCN2, Lenti-CON as control) into injured tibialis anterior muscle compromised regeneration capacity, resulting in significantly fewer CNFs in the Lenti-CCN2 group compared with Lenti-CON (488.07 ± 27.63 vs. 173.99 ± 14.28/mm2, P < 0.001) at 7 days post-injury (dpi). Conversely, knockdown of CCN2 (Lenti-CCN2shR, Lenti-NegsiR as control) in aged MuSCs improved regeneration capacity, significantly increasing the CNF count from 254.5 ± 26.36 to 560.39 ± 48.71/mm2. Lenti-CCN2 MuSCs also increased fibroblast proliferation and exacerbated skeletal muscle fibrosis, while knockdown of CCN2 in aged MuSCs mitigated this pattern. AICAR supplementation, mimicking exercise, replicated the beneficial effects of aerobic exercise by mitigating muscle weight decline, enhancing satellite cell activity and reducing fibrosis.
    CONCLUSIONS: Aerobic exercise effectively reverses the decline in endurance capacity and mitigates muscle atrophy in aged mice. It inhibits CCN2 secretion from senescent MuSCs, thereby enhancing skeletal muscle regeneration and preventing fibrosis in aged mice. AICAR supplementation mimics the beneficial effects of aerobic exercise.
    Keywords:  CCN2; MuSCs; aerobic exercise; aging; fibrosis; skeletal muscle
    DOI:  https://doi.org/10.1002/jcsm.13526
  33. Biochem Soc Trans. 2024 Jun 28. pii: BST20231066. [Epub ahead of print]
    A second generation of senotherapies: the development of targeted senolytics, senoblockers and senoreversers for healthy ageing.
    Vinesh Dhokia, Amal Albati, Hannah Smith, Gethin Thomas, Salvador Macip.
      Cellular senescence, a form of terminal cell cycle arrest, is as a key driver of organismal ageing and an important factor in age-related diseases. Insights into the senescent phenotype have led to the development of novel therapeutic strategies, collectively known as senotherapies, that aim to ameliorate the detrimental effects of senescent cell accumulation in tissues. The senotherapeutic field has rapidly evolved over the past decade, with clinical translation of the first drugs discovered currently underway. What began as the straightforward removal of senescent cells using repurposed compounds, which were given the name of senolytics, has grown into an expanding field that uses different state of the art approaches to achieve the goal of preventing the build-up of senescent cells in the body. Here, we summarize the emergence of a new generation of senotherapies, based on improving the efficacy and safety of the original senolytics by making them targeted, but also branching out into drugs that prevent senescence (senoblockers) or revert it (senoreversers).The use of nanotechnology, specific antibodies, cell-based approaches and restored immunosurveillance is likely to revolutionize the field of senotherapies in the near future, hopefully allowing it to realize its full clinical potential.
    Keywords:  senescence; senoblockers; senolytics; senoreversers; senotherapies
    DOI:  https://doi.org/10.1042/BST20231066
  34. bioRxiv. 2024 Jun 14. pii: 2024.06.12.598664. [Epub ahead of print]
    In Vivo Proximity Labeling Identifies a New Function for the Lifespan and Autophagy-regulating Kinase Pef1, an Ortholog of Human Cdk5.
    Haitao Zhang, Dongmei Zhang, Ling Li, Belinda Willard, Kurt W Runge.
      Cdk5 is a highly-conserved, noncanonical cell division kinase important to the terminal differentiation of mammalian cells in multiple organ systems. We previously identified Pef1, the Schizosaccharomyces pombe ortholog of cdk5, as regulator of chronological lifespan. To reveal the processes impacted by Pef1, we developed APEX2-biotin phenol-mediated proximity labeling in S. pombe. Efficient labeling required a short period of cell wall digestion and eliminating glucose and nitrogen sources from the medium. We identified 255 high-confidence Pef1 neighbors in growing cells and a novel Pef1-interacting partner, the DNA damage response protein Rad24. The Pef1-Rad24 interaction was validated by reciprocal proximity labeling and co-immunoprecipitation. Eliminating Pef1 partially rescued the DNA damage sensitivity of cells lacking Rad24. To monitor how Pef1 neighbors change under different conditions, cells induced for autophagy were labeled and 177 high-confidence Pef1 neighbors were identified. Gene ontology (GO) analysis of the Pef1 neighbors identified proteins participating in processes required for autophagosome expansion including regulation of actin dynamics and vesicle-mediated transport. Some of these proteins were identified in both exponentially growing and autophagic cells. Pef1-APEX2 proximity labeling therefore identified a new Pef1 function in modulating the DNA damage response and candidate processes that Pef1 and other cdk5 orthologs may regulate.
    DOI:  https://doi.org/10.1101/2024.06.12.598664
  35. Open Med (Wars). 2024 ;19(1): 20240986
    Investigating hormesis, aging, and neurodegeneration: From bench to clinics.
    Vittorio Calabrese, Uwe Wenzel, Tommaso Piccoli, Ursula M Jacob, Lidia Nicolosi, Giovanni Fazzolari, Gabriella Failla, Tilman Fritsch, Naomi Osakabe, Edward J Calabrese.
      Mitochondria-derived reactive oxygen species production at a moderate physiological level plays a fundamental role in the anti-aging signaling, due to their action as redox-active sensors for the maintenance of optimal mitochondrial balance between intracellular energy status and hormetic nutrients. Iron regulatory protein dysregulation, systematically increased iron levels, mitochondrial dysfunction, and the consequent oxidative stress are recognized to underlie the pathogenesis of multiple neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. Central to their pathogenesis, Nrf2 signaling dysfunction occurs with disruption of metabolic homeostasis. We highlight the potential therapeutic importance of nutritional polyphenols as substantive regulators of the Nrf2 pathway. Here, we discuss the common mechanisms targeting the Nrf2/vitagene pathway, as novel therapeutic strategies to minimize consequences of oxidative stress and neuroinflammation, generally associated to cognitive dysfunction, and demonstrate its key neuroprotective and anti-neuroinflammatory properties, summarizing pharmacotherapeutic aspects relevant to brain pathophysiology.
    Keywords:  C. elegans; Nrf2; antioxidants; hormesis; longevity; mitochondrial medicine
    DOI:  https://doi.org/10.1515/med-2024-0986
  36. Physiol Rep. 2024 Jun;12(12): e16094
    Renin-angiotensin system inhibitors positively impact on multiple aging regulatory pathways: Could they be used to protect against human aging?
    Elena M V de Cavanagh, Felipe Inserra, León Ferder.
      The renin-angiotensin system (RAS)-a classical blood pressure regulator-largely contributes to healthy organ development and function. Besides, RAS activation promotes age-related changes and age-associated diseases, which are attenuated/abolished by RAS-blockade in several mammalian species. RAS-blockers also increase rodent lifespan. In previous work, we discussed how RAS-blockade downregulates mTOR and growth hormone/IGF-1 signaling, and stimulates AMPK activity (together with klotho, sirtuin, and vitamin D-receptor upregulation), and proposed that at least some of RAS-blockade's aging benefits are mediated through regulation of these intermediaries and their signaling to mitochondria. Here, we included RAS-blockade's impact on other aging regulatory pathways, that is, TGF-ß, NF-kB, PI3K, MAPK, PKC, Notch, and Wnt, all of which affect mitochondria. No direct evidence is available on RAS/RAS-blockade-aging regulatory pathway-mitochondria interactions. However, existing results allow to conjecture that RAS-blockers neutralize mitochondrial dysfunction by acting on the discussed pathways. The reviewed evidence led us to propose that the foundation is laid for conducting clinical trials aimed at testing whether angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB)-even at subclinical doses-offer the possibility to live longer and in better health. As ACEi and ARB are low cost and well-tolerated anti-hypertension therapies in use for over 35 years, investigating their administration to attenuate/prevent aging effects seems simple to implement.
    Keywords:  RAS‐blockers; antiaging; mitochondria
    DOI:  https://doi.org/10.14814/phy2.16094
  37. Noncoding RNA. 2024 Jun 18. pii: 36. [Epub ahead of print]10(3):
    Molecular and Evolutionary Analysis of RNA-Protein Interactions in Telomerase Regulation.
    Justin A Davis, Kausik Chakrabarti.
      Telomerase is an enzyme involved in the maintenance of telomeres. Telomere shortening due to the end-replication problem is a threat to the genome integrity of all eukaryotes. Telomerase inside cells depends on a myriad of protein-protein and RNA-protein interactions to properly assemble and regulate the function of the telomerase holoenzyme. These interactions are well studied in model eukaryotes, like humans, yeast, and the ciliated protozoan known as Tetrahymena thermophila. Emerging evidence also suggests that deep-branching eukaryotes, such as the parasitic protist Trypanosoma brucei require conserved and novel RNA-binding proteins for the assembly and function of their telomerase. In this review, we will discuss telomerase regulatory pathways in the context of telomerase-interacting proteins, with special attention paid to RNA-binding proteins. We will discuss these interactors on an evolutionary scale, from parasitic protists to humans, to provide a broader perspective on the extensive role that protein-protein and RNA-protein interactions play in regulating telomerase activity in eukaryotes.
    Keywords:  RNA chaperones; RNA-binding proteins; Trypanosoma brucei; interactomes; parasites; telomerase; telomerase RNA; telomerase reverse transcriptase; telomeres
    DOI:  https://doi.org/10.3390/ncrna10030036
  38. Int J Mol Sci. 2024 Jun 20. pii: 6805. [Epub ahead of print]25(12):
    Role of Adipose-Derived Mesenchymal Stem Cells in Bone Regeneration.
    Chau Sang Lau, So Yeon Park, Lalith Prabha Ethiraj, Priti Singh, Grace Raj, Jolene Quek, Somasundaram Prasadh, Yen Choo, Bee Tin Goh.
      Bone regeneration involves multiple factors such as tissue interactions, an inflammatory response, and vessel formation. In the event of diseases, old age, lifestyle, or trauma, bone regeneration can be impaired which could result in a prolonged healing duration or requiring an external intervention for repair. Currently, bone grafts hold the golden standard for bone regeneration. However, several limitations hinder its clinical applications, e.g., donor site morbidity, an insufficient tissue volume, and uncertain post-operative outcomes. Bone tissue engineering, involving stem cells seeded onto scaffolds, has thus been a promising treatment alternative for bone regeneration. Adipose-derived mesenchymal stem cells (AD-MSCs) are known to hold therapeutic value for the treatment of various clinical conditions and have displayed feasibility and significant effectiveness due to their ease of isolation, non-invasive, abundance in quantity, and osteogenic capacity. Notably, in vitro studies showed AD-MSCs holding a high proliferation capacity, multi-differentiation potential through the release of a variety of factors, and extracellular vesicles, allowing them to repair damaged tissues. In vivo and clinical studies showed AD-MSCs favoring better vascularization and the integration of the scaffolds, while the presence of scaffolds has enhanced the osteogenesis potential of AD-MSCs, thus yielding optimal bone formation outcomes. Effective bone regeneration requires the interplay of both AD-MSCs and scaffolds (material, pore size) to improve the osteogenic and vasculogenic capacity. This review presents the advances and applications of AD-MSCs for bone regeneration and bone tissue engineering, focusing on the in vitro, in vivo, and clinical studies involving AD-MSCs for bone tissue engineering.
    Keywords:  adipose-derived stem cells; bone regeneration; bone tissue engineering; regenerative medicine
    DOI:  https://doi.org/10.3390/ijms25126805
  39. J Photochem Photobiol B. 2024 Jun 13. pii: S1011-1344(24)00117-9. [Epub ahead of print]257 112957
    Organic light-emitting diode therapy promotes longevity through the upregulation of SIRT1 in senescence-accelerated mouse prone 8 mice.
    Yue-Hua Deng, Chi-Sheng Chiou, Ching-Yu Tsai, Abhinay Kumar Singh, Edlin Anahi Pelaze Achtmann, Bou-Yue Peng, Tommy Yet-Min Lin, Hsin-Chung Cheng, Pao-Chang Chiang, Win-Ping Deng.
      Phototherapy has been extensively used to prevent and treat signs of aging and stimulate wound healing, and phototherapy through light-emitting diodes (LEDs). In contrast to LED, organic LED (OLED) devices are composed of organic semiconductors that possess novel characteristics. We investigated the regenerative potential of OLED for restoring cellular potential from senescence and thus delaying animal aging. Bone marrow-derived stem cells (BMSCs) and adipose-derived stem cells (ADSCs) were isolated from the control and OLED- treated groups to evaluate their proliferation, migration, and differentiation potentials. Cellular senescence was evaluated using a senescence-associated β-galactosidase (SA-β-gal) activity assay and gene expression biomarker assessment. OLED treatment significantly increased the cell proliferation, colony formation, and migration abilities of stem cells. SA-β-gal activity was significantly decreased in both ADSCs and BMSCs in the OLED-treated group. Gene expression biomarkers from treated mice indicated a significant upregulation of IGF-1 (insulin growthfactor-1). The upregulation of the SIRT1 gene inhibited the p16 and p19 genes then to downregulate the p53 expressions for regeneration of stem cells in the OLED-treated group. Our findings indicated that the survival rates of 10-month aging senescence-accelerated mouse prone 8 mice were prolonged and that their gross appearance improved markedly after OLED treatment. Histological analysis of skin and brain tissue also indicated significantly greater collagen fibers density, which prevents ocular abnormalities and β-amyloid accumulation. Lordokyphosis and bone characteristics were observed to resemble those of younger mice after OLED treatment. In conclusion, OLED therapy reduced the signs of aging and enhanced stem-cell senescence recovery and then could be used for tissue regeneration.
    Keywords:  Aging; Organic light-emitting diodes; Phototherapy; SIRT1; Stem cells reprogramming
    DOI:  https://doi.org/10.1016/j.jphotobiol.2024.112957
  40. Talanta. 2024 Jun 19. pii: S0039-9140(24)00826-9. [Epub ahead of print]278 126447
    Development of a versatile optical pH sensor array for discrimination of anti-aging face creams.
    Cheng Cheng, Enzo Terreno.
      The certification of cosmetic products has always been a prominent concern. Here, we have developed a pH sensor and applied it in the field of cosmetic safety. Initially, we designed two probes, CH with aggregation-induced emission (AIE) effect and the near-infrared fluorophore derivative CYTYR. By encapsulating them with DSPE-PEG2000-NH2, we obtained the CHCY-lipo nano-micelles with fluorescence resonance energy transfer (FRET) response. By combining them into a sensor array called pC, we achieved sensitive detection of a wide pH range, ranging from 4.69 to 9.25. To validate the performance of the pC sensor array, we employed a multi-channel mode and applied it to differentiate commercial anti-aging creams. Through linear discriminant analysis and 3D fingerprint analysis, the pC sensor array successfully distinguished anti-aging creams from different countries, providing a rapid and accurate method for cosmetic safety identification. The results of this study demonstrate the potential of the pC sensor array for quick authentication of cosmetic products, offering significant support and application prospects in safeguarding consumer health.
    Keywords:  Anti-aging creams; Consumer health; Cosmetic products; Fluorescence resonance energy transfer (FRET); pH sensor array
    DOI:  https://doi.org/10.1016/j.talanta.2024.126447
  41. Gene Ther. 2024 Jun 25.
    Highly efficient and specific regulation of gene expression using enhanced CRISPR-Cas12f system.
    Yeounsun Oh, Lee Wha Gwon, Hyomin K Lee, Junho K Hur, Kwang-Hyun Park, Kee-Pyo Kim, Seung Hwan Lee.
      The recently developed CRISPR activator (CRISPRa) system uses a CRISPR-Cas effector-based transcriptional activator to effectively control the expression of target genes without causing DNA damage. However, existing CRISPRa systems based on Cas9/Cas12a necessitate improvement in terms of efficacy and accuracy due to limitations associated with the CRISPR-Cas module itself. To overcome these limitations and effectively and accurately regulate gene expression, we developed an efficient CRISPRa system based on the small CRISPR-Cas effector Candidatus Woesearchaeota Cas12f (CWCas12f). By engineering the CRISPR-Cas module, linking activation domains, and using various combinations of linkers and nuclear localization signal sequences, the optimized eCWCas12f-VPR system enabled effective and target-specific regulation of gene expression compared with that using the existing CRISPRa system. The eCWCas12f-VPR system developed in this study has substantial potential for controlling the transcription of endogenous genes in living organisms and serves as a foundation for future gene therapy and biological research.
    DOI:  https://doi.org/10.1038/s41434-024-00458-w
  42. Metabolites. 2024 Jun 19. pii: 343. [Epub ahead of print]14(6):
    Nicotinamide N-Methyltransferase (NNMT): A New Hope for Treating Aging and Age-Related Conditions.
    Jing-Jing Li, Wei-Dong Sun, Xiao-Juan Zhu, Ya-Zhong Mei, Wen-Song Li, Jiang-Hua Li.
      The complex process of aging leads to a gradual deterioration in the function of cells, tissues, and the entire organism, thereby increasing the risk of disease and death. Nicotinamide N-methyltransferase (NNMT) has attracted attention as a potential target for combating aging and its related pathologies. Studies have shown that NNMT activity increases over time, which is closely associated with the onset and progression of age-related diseases. NNMT uses S-adenosylmethionine (SAM) as a methyl donor to facilitate the methylation of nicotinamide (NAM), converting NAM into S-adenosyl-L-homocysteine (SAH) and methylnicotinamide (MNA). This enzymatic action depletes NAM, a precursor of nicotinamide adenine dinucleotide (NAD+), and generates SAH, a precursor of homocysteine (Hcy). The reduction in the NAD+ levels and the increase in the Hcy levels are considered important factors in the aging process and age-related diseases. The efficacy of RNA interference (RNAi) therapies and small-molecule inhibitors targeting NNMT demonstrates the potential of NNMT as a therapeutic target. Despite these advances, the exact mechanisms by which NNMT influences aging and age-related diseases remain unclear, and there is a lack of clinical trials involving NNMT inhibitors and RNAi drugs. Therefore, more in-depth research is needed to elucidate the precise functions of NNMT in aging and promote the development of targeted pharmaceutical interventions. This paper aims to explore the specific role of NNMT in aging, and to evaluate its potential as a therapeutic target.
    Keywords:  aging-associated diseases; cancer; cardiovascular diseases; diabetes; homocysteine (Hcy); neurodegenerative diseases; nicotinamide N-methyltransferase (NNMT); nicotinamide adenine dinucleotide (NAD+)
    DOI:  https://doi.org/10.3390/metabo14060343
  43. bioRxiv. 2024 Jun 14. pii: 2024.06.14.599036. [Epub ahead of print]
    Comparison of Age-Related Decline and Behavioral Validity in C57BL/6 and CB6F1 Mice.
    Gerald Yu Liao, Christina Pettan-Brewer, Warren Ladiges.
      Variability in physical resilience to aging prompts a comprehensive examination of underlying mechanisms across organs and individuals. We conducted a detailed exploration of behavioral and physiological differences between C57BL/6 and CB6F1 mice across various age groups. In behavioral assays, B6 mice displayed superior performance in rotarod tasks but higher anxiety while CB6F1 mice exhibited a decline in short-term memory with age. Grip strength, long-term memory, and voluntary wheel running declined similarly with age in both strains. Examining physiological phenotypes, B6 mice exhibited lower body fat percentages across ages compared to CB6F1 mice, though cataract severity worsened with age in both strains. Analysis of cardiac functions revealed differences between strains, with worsening left ventricular hypertrophy and structural heart abnormalities with age in CB6F1 mice along with higher blood pressure than B6. Lesion scores showed an age-related increase in heart, kidney, and liver lesions in both strains, while lung lesions worsened with age only in CB6F1 mice. This study underscores the validity of behavioral assays and geropathology assessment in reflecting age-related decline and emphasizes the importance of considering strain specificity when using mouse models to study human aging.
    DOI:  https://doi.org/10.1101/2024.06.14.599036
  44. Aging Dis. 2024 Jun 07.
    Cellular Aging and Senescence in Cancer: A Holistic Review of Cellular Fate Determinants.
    Muhammad Tufail, Yu-Qi Huang, Jia-Ju Hu, Jie Liang, Cai-Yun He, Wen-Dong Wan, Can-Hua Jiang, Hong Wu, Ning Li.
      This comprehensive review navigates the complex relationship between cellular aging, senescence, and cancer, unraveling the determinants of cellular fate. Beginning with an overview of cellular aging's significance in cancer, the review explores processes, changes, and molecular pathways influencing senescence. The review explores senescence as a dual mechanism in cancer, acting as a suppressor and contributor, focusing on its impact on therapy response. This review highlights opportunities for cancer therapies that target cellular senescence. The review further examines the senescence-associated secretory phenotype and strategies to modulate cellular aging to influence tumor behavior. Additionally, the review highlights the mechanisms of senescence escape in aging and cancer cells, emphasizing their impact on cancer prognosis and resistance to therapy. The article addresses current advances, unexplored aspects, and future perspectives in understanding cellular aging and senescence in cancer.
    DOI:  https://doi.org/10.14336/AD.2024.0421
  45. Commun Chem. 2024 Jun 27. 7(1): 145
    Tracking DOT1L methyltransferase activity by stable isotope labelling using a selective synthetic co-factor.
    Nicole Trainor, Harry J Whitwell, Beatriz Jiménez, Katie Addison, Emily Leonidou, Peter A DiMaggio, Matthew J Fuchter.
      Epigenetic processes influence health and disease through mechanisms which alter gene expression. In contrast to genetic changes which affect DNA sequences, epigenetic marks include DNA base modifications or post-translational modification (PTM) of proteins. Histone methylation is a prominent and versatile example of an epigenetic marker: gene expression or silencing is dependent on the location and extent of the methylation. Protein methyltransferases exhibit functional redundancy and broad preferences for multiple histone residues, which presents a challenge for the study of their individual activities. We developed an isotopically labelled analogue of co-factor S-adenosyl-L-methionine (13CD3-BrSAM), with selectivity for the histone lysine methyltransferase DOT1L, permitting tracking of methylation activity by mass spectrometry (MS). This concept could be applied to other methyltransferases, linking PTM discovery to enzymatic mediators.
    DOI:  https://doi.org/10.1038/s42004-024-01227-x
  46. Mol Biol Evol. 2024 Jun 25. pii: msae131. [Epub ahead of print]
    Discovering fragile clades and causal sequences in phylogenomics by evolutionary sparse learning.
    Sudip Sharma, Sudhir Kumar.
      Phylogenomic analyses of long sequences, consisting of many genes and genomic segments, infer organismal relationships with high statistical confidence. But, these relationships can be sensitive to excluding just a few sequences. Currently, there is no direct way to identify fragile relationships and the associated individual gene sequences in species. Here, we introduce novel metrics for gene-species sequence concordance and clade probability derived from evolutionary sparse learning models. We validated these metrics using fungi, plant, and animal phylogenomic datasets, highlighting the ability of the new metrics to pinpoint fragile clades and the sequences responsible. The new approach does not necessitate the investigation of alternative phylogenetic hypotheses, substitution models, or repeated data subset analyses. Our methodology offers a streamlined approach to evaluating major inferred clades and identifying sequences that may distort reconstructed phylogenies using large datasets.
    Keywords:  Phylogenomics; clade support; evolutionary sparse learning; machine learning
    DOI:  https://doi.org/10.1093/molbev/msae131
This page is being maintained by Thomas Krichel. It was last updated on 2024‒08‒10 at 19:08.