bims-caglex 2025-07-06 papers

bims-caglex

Biomed News

on Cellular aging and life extension

Issue of 2025–07–06
seventeen papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño

Chemical reprogramming ameliorates cellular hallmarks of aging and extends lifespan.
Comparison of MSCs and Muse cells: the possible use for healthspan optimization.
Recent advances in dermal fibroblast senescence and skin aging: unraveling mechanisms and pioneering therapeutic strategies.
Environmental factors capable of broadly interfering with nutritional lifespan extension paradigms.
Small extracellular vesicles derived from mesenchymal stromal cells loaded with β-nicotinamide mononucleotide activate NAD+/SIRT3 signaling pathway-mediated mitochondrial autophagy to delay skin aging.
Emerging uncertainty on the anti-aging potential of metformin.
Pharmacological modulation of stem cells signaling pathway for therapeutic applications.
Tissue nanotransfection and cellular reprogramming in regenerative medicine and antimicrobial dynamics.
Nanosecond pulsed electric field applications rejuvenate aging endothelial cells by rescuing mitochondrial-to-nuclear retrograde communication.
Novel Cyclized Hexapeptide-9 Outperforms Retinol Against Skin Aging: A Randomized, Double-Blinded, Active- and Vehicle-Controlled Clinical Trial.
Tailored Extracellular Vesicles from Dental Stem Cells: Advances in Specific Modifications for Enhanced Therapeutic Applications.
An overview of contemporary theories of ageing.
Epigenetic Regulation of Bone Healing: Implications for Fracture Repair and Clinical Treatment Strategies.
Reprogramming cellular senescence of hepatic stellate cells to combat liver fibrosis by targeted nanodrugs.
15-PGDH inhibition enhances hematopoietic regeneration during aging.
Vector-free intra-airway in vivo epigenetic editing.
Profiling Epigenetic Aging at Cell-Type Resolution Through Long-Read Sequencing.

EMBO Mol Med. 2025 Jun 30.

Chemical reprogramming ameliorates cellular hallmarks of aging and extends lifespan.

Lucas Schoenfeldt, Patrick T Paine, Sara Picó, Nibrasul H Kamaludeen M, Grace B Phelps, Calida Mrabti, Gabriela Desdín-Micó, María Del Carmen Maza, Kevin Perez, Alejandro Ocampo.

  The dedifferentiation of somatic cells into a pluripotent state by cellular reprogramming coincides with a reversal of age-associated molecular hallmarks. Although transcription factor induced cellular reprogramming has been shown to ameliorate these aging phenotypes in human cells and extend health and lifespan in mice, translational applications of this approach are still limited. More recently, chemical reprogramming via small molecule cocktails have demonstrated a similar ability to induce pluripotency in vitro, however, its potential impact on aging is unknown. Here, we demonstrated that chemical-induced partial reprogramming can improve key drivers of aging including genomic instability and epigenetic alterations in aged human cells. Moreover, we identified an optimized combination of two reprogramming molecules sufficient to induce the amelioration of additional aging phenotypes including cellular senescence and oxidative stress. Importantly, in vivo application of this two-chemical combination significantly extended C. elegans lifespan and healthspan. Together, these data demonstrate that improvement of key drivers of aging and lifespan extension is possible via chemical-induced partial reprogramming, opening a path towards future translational applications.

Keywords:  Aging; Cellular Reprogramming; Chemical Reprogramming; Epigenetics; Lifespan

DOI:  https://doi.org/10.1038/s44321-025-00265-9
Biogerontology. 2025 Jul 02. 26(4): 139

Comparison of MSCs and Muse cells: the possible use for healthspan optimization.

Mari Dezawa.

  The exploration for safe, effective intervention strategies to improve longevity and aging-related diseases is attracting attention to prolong the healthy lifespan. Since aging is based on cellular changes, including telomere attrition, DNA damage, and mitochondrial dysfunction, therapies related to stem cells are expected to be a rational strategy for solving aging problems at the cellular level. Mesenchymal stem cells (MSCs) are an easily accessible, safe candidate, as they supply paracrine factors and extracellular vesicles to deliver pleiotropic effects for aging tissues. Multilineage-differentiating stress enduring (Muse) cells represent endogenous, reparative macrophage-like/pluripotent-like stem cells distributed in various tissues, including extraembryonic tissues such as the umbilical cord, and are also found in MSCs as a small percentage of the total population. Muse cell characteristics are different from those of MSCs. Intravenously injected Muse cells sharply sense the universal damage signal sphingosine-1-P and selectively migrate to damaged tissue rather than being trapped in the lung, phagocytose damaged/apoptotic cells in the tissue and directly differentiate into the same cell type. Muse cells then repair the three dimensional structure of the tissue by replacing multiple tissue component with healthy cells through pluripotent-like differentiation. Clinical trials have shown that HLA-mismatched donor Muse cells escape immune rejection and survive in the recipient tissue for an extended period without immunosuppressant treatment. Therefore, the pleiotropic bystander effects of Muse cells are more potent than those of MSCs. Due to heterogeneity, the properties of MSCs are still not fully understood; they have limited differentiation ability into osteogenic, chondrogenic, and adipogenic cells, and the main biological action in vivo is bystander effects. Muse cells are key, not only to the medical benefits of MSCs, but also to their potential use in anti-aging therapy. Enriching and purifying Muse cells will significantly enhance the therapeutic effect of MSCs, leading to further expansion of the use of MSCs. This review discusses the fundamental differences between MSCs and Muse cells and their potential applications in anti-aging therapy.

Keywords:  Cell replacement; Immunotolerance; Intravenous injection; Phagocytosis; Sphingosine-1-P; Tissue rejuvenation; Tissue repair

DOI:  https://doi.org/10.1007/s10522-025-10275-2
Front Pharmacol. 2025 ;16 1592596

Recent advances in dermal fibroblast senescence and skin aging: unraveling mechanisms and pioneering therapeutic strategies.

Li Nan, Pengchao Guo, Wang Hui, Fang Xia, Chenggang Yi.

  Aging is a multifactorial process that affects skin integrity through the progressive decline of dermal fibroblast function. Dermal fibroblasts are key regulators of extracellular matrix (ECM) composition, wound healing, and tissue homeostasis. However, their dysfunction contributes to structural deterioration, chronic inflammation, and impaired regenerative capacity. Cellular senescence, a fundamental characteristic of aging, results in the buildup of senescent fibroblasts that release growth factors, matrix-degrading enzymes, and pro-inflammatory cytokines, known as the senescence-associated secretory phenotype (SASP). This study examines the impact of fibroblast senescence on dermal aging, highlighting mechanisms such as DNA damage, mitochondrial dysfunction, oxidative stress, and telomere attrition. The role of SASP-driven ECM degradation, matrix metalloproteinases (MMPs) activation, and fibroblast-keratinocyte communication breakdown are explored, demonstrating their collective contribution to skin aging. Additionally, key signaling pathways, including p16INK4a/RB, p53, NF-κB, mTOR, and TGF-β, are implicated in fibroblast senescence and chronic inflammation. Recent advancements in therapeutic strategies targeting fibroblast aging, such as senolytics, extracellular vesicle-based interventions, and metabolic reprogramming, offer promising avenues for skin rejuvenation. This review delves into the molecular and cellular dynamics of dermal fibroblast aging, emphasizing their relevance for developing novel anti-aging interventions.

Keywords:  SASP; aging; dermal fibroblast; signaling pathways; skin

DOI:  https://doi.org/10.3389/fphar.2025.1592596
iScience. 2025 Jul 18. 28(7): 112827

Environmental factors capable of broadly interfering with nutritional lifespan extension paradigms.

Sainan Li, Nicole L Stuhr, Fasih Ahsan, Yifei Zhou, Armen Yerevanian, Jen Rotti, Khoi Dao, Mohit Jain, Alexander A Soukas.

  Despite being principally prescribed to treat type 2 diabetes, biguanides, especially metformin and phenformin, have been shown to extend lifespan and healthspan in preclinical models. Although there have been conflicting results in studies involving rodents and humans, consistent evidence indicates metformin and phenformin's ability to significantly extend lifespan in Caenorhabditis elegans. We find that variation in agar from lot-to-lot or from different manufacturers influences metformin's ability to extend lifespan in diverse Caenorhabditis species. Using unbiased metabolomics and genetics, we traced the ability of certain agars to interfere with metformin-prompted lifespan extension to differences in glucose, dipeptide, and trace element levels. These compounds act directly in the worm, independently of the bacterial food source, preventing longevity through action downstream of longevity effectors skn-1 and AMPK. In contrast, phenformin prompts robust lifespan extension in the face of environmental changes and exhibits broad positive effects in aging across genetically diverse Caenorhabditis species.

Keywords:  Biological sciences; Metabolomics; Pharmacology

DOI:  https://doi.org/10.1016/j.isci.2025.112827
Stem Cell Res Ther. 2025 Jul 01. 16(1): 339

Small extracellular vesicles derived from mesenchymal stromal cells loaded with β-nicotinamide mononucleotide activate NAD+/SIRT3 signaling pathway-mediated mitochondrial autophagy to delay skin aging.

Zixuan Sun, Jiali Li, Yuzhou Zheng, Jiaxin Zhang, Wenhuan Bai, Xinyi Deng, Zhijing Wu, XueZhong Xu, Wei Ding, Hui Qian, Yulin Tan.

   BACKGROUND: Recently, the beneficial effects of human umbilical cord mesenchymal stromal cell (hucMSC)-derived small extracellular vesicles (sEVs) in mitigating skin aging through multiple mechanisms have been widely reported. β-Nicotinamide mononucleotide (NMN) is an iconic anti-aging drug that increases NAD+ levels in the body to slow down, ameliorate, and prevent various phenotypes associated with aging, but its high water solubility, low permeability, and instability limit its clinical application. Based on this, we applied electroporation to construct NMN-loaded hucMSC-sEVs (NMN-sEVs) to improve their stability and efficacy and to enhance their potential for translational application in medical aesthetics and anti-aging.
METHODS: D-galactose was applied to construct a mouse skin aging model, based on which comparative analyses of topical and nano-microneedle administration were performed to determine the optimal delivery method of sEVs in vivo experiments. After constructing NMN-sEVs by electroporation, high-performance liquid chromatography was applied to detect the loading efficiency, and the effects of NMN-sEVs on delaying skin aging were assessed by histological analysis. In addition, the defense effects of NMN-sEVs against cellular senescence were verified by reactive oxygen species assay, β-galactosidase staining, qRT-PCR, Western blot, and cellular immunofluorescence. Finally, the roles of NMN-sEVs in remodeling mitochondrial function and delaying cellular senescence through mitochondrial autophagy were assessed by mitochondrial mass, function, and autophagy level assays.
RESULTS: Our data suggested that NMN-sEVs could improve skin aging in mice, delay cellular senescence, and restore cellular mitochondrial dysfunction. Notably, NMN-sEVs treatment increased intracellular NAD+ levels and SIRT3 expression, as well as rescued the inhibition of senescence-induced mitochondrial autophagy, suggesting a role for NMN-sEVs in the remodeling of mitochondrial function through mitochondrial autophagy. Additionally, the use of the SIRT3 inhibitor 3-TYP suppressed the positive effects of NMN-sEVs on cellular senescence, mitochondrial function, and mitochondrial autophagy while restoring senescence-associated characteristics.
CONCLUSION: Overall, our findings revealed a mechanism by which NMN-sEVs attenuated mitochondrial dysfunction and rescued cellular senescence by promoting NAD+/SIRT3 pathway-mediated mitophagy and might provide a promising strategy for anti-aging pharmaceuticals.

Keywords:  HucMSC-sEVs; Mitochondrial autophagy; NMN; SIRT3; Skin aging

DOI:  https://doi.org/10.1186/s13287-025-04460-w
Ageing Res Rev. 2025 Jun 27. pii: S1568-1637(25)00163-1. [Epub ahead of print] 102817

Emerging uncertainty on the anti-aging potential of metformin.

Matthew Thomas Keys, Jesper Hallas, Richard A Miller, Samy Suissa, Kaare Christensen.

  Metformin is the most commonly prescribed glucose-lowering agent worldwide for the treatment of type II diabetes. Due to evidence of improvements in healthspan and lifespan in model organisms, and mechanistic data relevant to the hallmarks of aging, it has been considered a promising candidate in the search for pharmacological interventions that may attenuate the ageing process in humans. Various epidemiological studies have been influential in generating support for this hypothesis. These include pronounced anticancer and cardioprotective benefits compared to other antidiabetic treatments, and an observation of metformin use in type II diabetes being associated with better survival than that of the general population. Here we discuss recent developments in the evidence underlying the rationale for using metformin to target ageing. We describe the methodological limitations of some of the early and most influential findings and critically assess their scientific follow-up, including replication attempts of key experimental and observational findings, and a range of clinical trials of metformin in individuals without type II diabetes. These developments generally illustrate an emerging uncertainty in the anti-aging potential of metformin.

Keywords:  anti-aging; geroprotective; lifespan; longevity; metformin; type 2 diabetes

DOI:  https://doi.org/10.1016/j.arr.2025.102817
Stem Cell Res Ther. 2025 Jul 01. 16(1): 327

Pharmacological modulation of stem cells signaling pathway for therapeutic applications.

Sulaiman Mohammed Alnasser, Abdulrahman Saleh Alrobian, Mohammad Salem Alfayez, Omar Tuwayli Almutairi, Saud Saeed Almutairi, Talal Sami Alkeraidees.

  Stem cells have an exceptional capacity for self-renewal and differentiation and are at the forefront of therapeutics, offering promising solutions for repairing tissues, cancer treatment and the cure of degenerative diseases. Stem cell fate is tightly regulated by key signaling pathways like Hedgehog, TGF-β, Wnt, Hippo, FGF, BMP and Notch, making these pathways prime targets for precision interventions. Despite significant advancements, challenges such as immune rejection, tumorigenesis, and inefficient tissue integration continue to limit clinical success. Pharmacological strategies are emerging as powerful tools to overcome these barriers by enhancing stem cell survival, directing differentiation, and modulating the stem cell niche. Small molecules can activate endogenous stem cells, reducing the need for transplantation while promoting in situ regeneration. Additionally, advancements in gene-editing technologies and biomaterials are further refining stem cell-based therapies. This paves the way for safer, more effective, and personalized therapies. Nevertheless, transforming these innovations into clinical practice entails overcoming regulatory hurdles, optimizing delivery methods, and ensuring long-term safety and efficacy. A multidisciplinary approach integrating personalized medicine, pharmacological modulation, and tissue engineering holds the key to addressing these limitations. Advancing research and refining previous strategies utilizing stem cell therapies has the prospective to revolutionize regenerative and onco-medicine, providing more targeted and sustainable treatment options for a wide range of diseases.

Keywords:  Medicine; Pharmacological modulation; Signaling pathways; Stem cell therapy

DOI:  https://doi.org/10.1186/s13287-025-04438-8
Front Bioeng Biotechnol. 2025 ;13 1558735

Tissue nanotransfection and cellular reprogramming in regenerative medicine and antimicrobial dynamics.

Mohammed Youssef Shakra.

  Tissue nanotransfection (TNT) is a novel, non-viral nanotechnology platform that enables in vivo gene delivery and direct cellular reprogramming through localized nanoelectroporation. This review synthesizes current advancements in TNT, outlining its device architecture, electroporation principles, and optimized delivery of genetic cargo, including plasmid DNA, mRNA, and CRISPR/Cas9 components. The mechanisms underlying TNT-mediated cellular reprogramming are critically evaluated, including transcriptional activation, epigenetic remodeling, and metabolic shifts, across three major reprogramming strategies-induced pluripotency, direct lineage conversion, and partial cellular rejuvenation. TNT demonstrates transformative therapeutic potential in diverse biomedical applications, including tissue regeneration, ischemia repair, wound healing, immunotherapy, and antimicrobial therapy. This review highlights TNT's unique advantages over traditional gene delivery systems, namely, its high specificity, non-integrative approach, and minimal cytotoxicity, while also addressing existing limitations such as phenotypic stability and scalability. By integrating emerging data and identifying key translation challenges, this work positions TNT as a conceptual and technological advance in regenerative medicine and targeted gene therapy, offering a roadmap for future research and clinical implementation.

Keywords:  antimicrobial; cellular reprogramming; regenerative medicine; tissue nanotransfection; wound healing

DOI:  https://doi.org/10.3389/fbioe.2025.1558735
Regen Ther. 2025 Dec;30 207-216

Nanosecond pulsed electric field applications rejuvenate aging endothelial cells by rescuing mitochondrial-to-nuclear retrograde communication.

Meifang Yin, Jie Xiao, Guangtao Huang, Huanyu Xie, Hongwei Liu, Jianqiang Yuan, Xiaofang Liu, Anna Chiarini, Ubaldo Armato, Ilaria Dal Prà, Shumaila Ijaz, Naziat Begum, Lingyun Wang, Jun Wu.

   Introduction: Endothelial cell aging is strongly associated with mitochondrial dysfunction, particularly the disruption of mitochondrial-nuclear retrograde communication (MNRC), which is essential for sustaining cellular homeostasis and regulating crucial cellular processes. Nanosecond pulsed electric fields (nsPEF) were shown to exert biological effects by targeting mitochondria. However, the nsPEF regulation of MNRC is still unclear.
Methods: In this study, we set up an in vitro model of d-galactose-induced senescence in human umbilical vein endothelial cells (HUVECs) to investigate the effects of nsPEF treatment on oxidative stress, cell proliferation, mitochondrial membrane potential, and markers of MNRC (MNRC), including HIF-1α and SIRT1. Moreover, we conducted in vivo animal experiments to evaluate nsPEF treatment's effects on HIF-1α and SIRT1 protein expression in endothelial cells (ECs) of in vivo rodents' aging/senescing skin tissue, as well as to examine any later changes in vascular density within the skin.
Results: In vitro results showed that nsPEF treatment suppressed d-galactose-induced senescing effects as they rescued mitochondrial membrane potential, and activated HIF-1α and SIRT1. These effects were confirmed by concurrent reductions in SA-β-Gal activity and in ROS production, and increases in EdU-positive (DNA-synthesizing) cells. Our data showed that nsPEF treatments rescued endothelial cells from d-galactose senescence. Interestingly, nsPEF selectively targeted senescing cells at the tested dose, with no detectable effect on otherwise untreated (normal) HUVECs. In vivo nsPEF treatments upregulated the expression of HIF-1α and SIRT1 in ECs and promoted neoangiogenesis in aged/senescent rodents' skin.
Conclusions: These findings suggest that nsPEF treatments rescue ECs from aging by restoring MNRC, highlighting its potential as a therapeutic strategy for age-related vascular diseases.

Keywords:  Endothelial aging; Mitochondrial-nuclear communication; Nanosecond pulsed electric field; Oxidative stress; Vascular regeneration

DOI:  https://doi.org/10.1016/j.reth.2025.06.004
J Cosmet Dermatol. 2025 Jul;24(7): e70290

Novel Cyclized Hexapeptide-9 Outperforms Retinol Against Skin Aging: A Randomized, Double-Blinded, Active- and Vehicle-Controlled Clinical Trial.

Huailong Chang, Kan Tao, Yuge Yang, Yanling Wang, Mengru Ge, Xiaoli Wang, Shengnan Tang, Haining Yu.

   BACKGROUND: The functionality and regenerative capacity of skin progressively deteriorate with aging. Topical use of peptides with a hyper-safety profile has been implicated in replacing retinol for skin anti-aging use, but is limited due to low stability and poor skin permeability.
AIMS: In this randomized, double-blinded, active- and vehicle-controlled clinical trial, we aim to evaluate the efficacy of an innovative cyclized hexapeptide-9 (CHP-9) with increased stability and skin permeability on skin aging compared to retinol.
METHODS: Healthy volunteers with aging skin were randomly assigned to twice-daily topical use of 0.002% CHP-9 serum, 0.002% retinol serum, or vehicle serum for 56 days.
RESULTS: CHP-9 treatment significantly decreased the number, area, and roughness of both crow's feet (-2.20, 95% CI: -4.38, -0.03; -3.95, 95% CI: -5.80, -2.11; -1.95, 95% CI: -3.30, -0.59, respectively) and forehead wrinkles (-2.88, 95% CI: -4.21, -1.56; -4.90, 95% CI: -5.97, -3.82; -3.96, 95% CI: -5.92, -2.01, respectively), while retinol only decreased the area of crow's feet (-2.23, 95% CI: -3.86, -0.60) and the number and area of forehead wrinkles (-1.05, 95% CI:-1.69, -0.41). Except for the roughness of crow's feet, CHP-9 demonstrated significantly larger extent of effects than retinol did on all other outcomes. Furthermore, long-term use of CHP-9 showed time-dependent augmentation in its potency to reduce the number of crow's feet, and the number, area, and roughness of forehead wrinkles.
CONCLUSIONS: In conclusion, CHP-9 is more potent than retinol in improving skin aging-related symptoms, especially for long-term use. Cyclization of collagen peptides may present a preventive/therapeutic option for skin aging.

Keywords:  clinical trial; cyclized hexapeptide‐9; efficacy evaluation; retinol; skin aging; wrinkles

DOI:  https://doi.org/10.1111/jocd.70290
Int J Nanomedicine. 2025 ;20 8327-8341

Tailored Extracellular Vesicles from Dental Stem Cells: Advances in Specific Modifications for Enhanced Therapeutic Applications.

Xiaojing Liu, Ziwei Li, Jiao Fu, RuoXuan Wang, Jihui He, Juming Yao, Qingsong Ye, Yan He.

  Extracellular vesicles(EVs) derived from dental stem cells have emerged as a key focus in regenerative medicine, owing to their remarkable ability to promote tissue repair and regeneration. Recent advancements revealed that targeted modifications can significantly boost their functional properties, creating new possibilities for the regeneration field. This article provides an overview of the most recent progress in EVs derived from dental stem cells research, with a particular emphasis on diverse engineering strategies such as genetic, chemical, and physical techniques, and their role in enhancing therapeutic performance. Furthermore, the influence of these engineering methods on the yield of EVs is thoroughly examined, offering critical perspectives for improving large-scale manufacturing efficiency. Pretreatment-generated conditioned dental stem cells-derived EVs are also explored as an innovative approach, demonstrating superior biological functions and regenerative potential. By integrating contemporary findings, this review underscores the superior capabilities of modified EVs derived from dental stem cells in driving progress in regenerative medicine and lays the groundwork for future investigations focused on clinical applications and therapeutic innovation.

Keywords:  extracellular vesicles; hypoxia; inflammation; preconditioning; predifferentiation; regeneration

DOI:  https://doi.org/10.2147/IJN.S528190
Nat Cell Biol. 2025 Jul 01.

An overview of contemporary theories of ageing.

João Pedro de Magalhães.

Ageing is a complex biological process whose underlying mechanisms remain contentious. Nonetheless, due to an ageing global population and the rising incidence of age-related diseases, understanding why we age is one of the most important scientific questions of our time, with profound medical implications. Here, I explore the fundamental nature of the ageing process and provide an overview of modern mechanistic theories. I critically examine two main groups of ageing theories: error-based and program-based theories. I discuss the relevance of these theories in the context of ageing patterns, genetic manipulations and longevity drugs, highlighting how experimental challenges and technological limitations have hindered progress. Overall, there is a pressing and unmet need for a robust theoretical framework in ageing research. Elucidating the cellular and molecular mechanisms of ageing would be crucial for developing effective interventions that slow the ageing process and prevent its associated diseases.

DOI: https://doi.org/10.1038/s41556-025-01698-7
Yale J Biol Med. 2025 Jun;98(2): 159-170

Epigenetic Regulation of Bone Healing: Implications for Fracture Repair and Clinical Treatment Strategies.

Sathya Subramoniam Iyer.

  Bone healing and fracture repair are complex processes involving multiple phases that rely on coordination and differentiation of multiple cell types, such as mesenchymal stem cells (MSCs), osteoblasts, osteoclasts, chondrocytes, and endothelial cells. The functions of growth factor and mechanical force in bone regeneration are well established, but recent research has revealed epigenetic mechanisms to play a major role in regulating cellular differentiation and tissue repair. Various studies have indicated epigenetic mechanisms like DNA methylation, histone modifications, and regulation by non-coding RNAs (ncRNA) are responsible for major gene expression regulation during bone regeneration. Moreover, systemic factors such as inflammation, aging, and metabolic disturbances regulate epigenetic regulation of bone cells to result in defective fracture healing. Emerging concepts in epigenetic therapy reveal new approaches to optimize bone regeneration and improve clinical results. This review focuses on the role of epigenetic regulation in the process of bone healing, highlighting its clinical implications.

Keywords:  DNA methylation; bone healing; epigenetic regulation; epigenetic therapies; fracture repair; histone modifications; mesenchymal stem cells; non-coding RNAs; osteogenesis

DOI:  https://doi.org/10.59249/HSYL8000
Mater Today Bio. 2025 Aug;33 101996

Reprogramming cellular senescence of hepatic stellate cells to combat liver fibrosis by targeted nanodrugs.

Bingyuan Fei, Hui Wang, Yu Ding, Nannan Shao, Panyue Wen, Yanwei Cao, Junjie Li, Masaru Tanaka, Zheng Wang, Shuo Li.

  Senescence of activated hepatic stellate cells (aHSCs) is thought to be a promising alternative for limiting hepatic fibrosis. However, uncontrollable accumulation and spread of senescence in neighboring hepatocytes lead to inflammation and steatosis, aggravating fibrosis and even promoting carcinogenesis. To harness senescence for fibrotic treatment, aHSCs-targeted poly (lactic-co-glycolic acid) (PLGA) nanoplatforms have been constructed to integrate senescent induction of aHSCs and senescent reprogramming. Owing to the CD44 aptamer modification, the nanoplatform specifically delivers senescent inducers and small interfering RNAs (siRNAs) that silence nuclear factor-kappa B (NF-κB) in aHSCs, thereby inducing senescence and simultaneously suppressing the production of senescence-associated secretory phenotypes (SASPs) in aHSCs. The senescence of aHSCs decreases their proliferation, and achieves permanent inactivation even upon repeated fibrotic stimulus. Meanwhile, the elimination of SASPs interrupts the vicious cycle of senescent aHSCs with surrounding hepatocytes to decrease senescent and inflammatory accumulation in liver tissues. In vitro and in vivo results confirmed the superior ability of the nanoplatform to inhibit liver fibrosis and control the spread of senescence. Our work provides a nanoplatform for specifically inducing senescence of aHSCs and reveals a promising senescence modulation strategy for the treatment of liver fibrosis.

Keywords:  Hepatic stellate cell; Liver fibrosis nanodrug; Natural killer cells; Senescence

DOI:  https://doi.org/10.1016/j.mtbio.2025.101996
Stem Cells. 2025 Jul 03. pii: sxaf047. [Epub ahead of print]

15-PGDH inhibition enhances hematopoietic regeneration during aging.

Rahul Chaudhary, Brittany A Cordova, Marcus Hong, Bailey R Klein, Lyannah A Contreras, Ritisha Rashmil, Filip Goshevski, Julianne N P Smith, Derek J Taylor, Andrew A Pieper, Sanford Markowitz, Amar B Desai.

  Hematopoietic aging is characterized by diminished stem cell regenerative capacity and an increased risk of hematologic dysfunction. We previously identified that the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) regulates hematopoietic stem cell activity. Here, we expand on this work and demonstrate that in aged mice, (1) 15-PGDH expression and activity remain conserved in the bone marrow and spleen, suggesting it remains a viable therapeutic target in aging, (2) prolonged PGDH inhibition (PGDHi) significantly increases the frequency and number of phenotypic hematopoietic stem and progenitor cells across multiple compartments, with transcriptional changes indicative of enhanced function, (3) PGDHi-treated bone marrow enhances short-term hematopoietic recovery following transplantation, leading to improved peripheral blood output and accelerated multilineage reconstitution, and (4) PGDHi confers a competitive advantage in primary hematopoietic transplantation while mitigating age-associated myeloid bias in secondary transplants. Notably, these effects occur without perturbing steady-state blood production, suggesting that PGDHi enhances hematopoiesis under regenerative conditions while maintaining homeostasis. Our work identifies PGDHi as a translatable intervention to rejuvenate aged HSCs and mitigate hematopoietic decline.

Keywords:  aging; drug target; hematopoietic stem cell transplantation; hematopoietic stem cells; stem cells

DOI:  https://doi.org/10.1093/stmcls/sxaf047
Trends Biotechnol. 2025 Jun 09. pii: S0167-7799(25)00173-8. [Epub ahead of print]

Vector-free intra-airway in vivo epigenetic editing.

Naohiro Yano, Mohankumar Ramar, David J Gregory, Alexey V Fedulov.

  Targeted, promoter-specific removal of DNA methylation marks is emerging as a promising strategy for experimental and therapeutic regulation of gene expression. Research to date has relied largely on the expression of transgene-encoded epigenetic editor constructs in target cells. While effective for in vitro demonstrations, alternative approaches are needed for greater translatability to humans. Here, we describe the design of recombinant, gene-targeted epigenetic editor proteins that are directly taken up by mouse lung cells following administration in vivo without transgenesis, vectors, or packaging tools. Proteins are targeted to their intended promoter using either dCas9 or artificial zinc finger domains, and thymine-DNA-glycosylase (TDG) and ten-eleven translocation proteins (Tet) catalytic domains mediate specific demethylation. Results demonstrate intranuclear arrival of epigenetic editors in vitro and in mice, local DNA demethylation, and resulting highly gene-specific derepression of the transcriptional response, which confers sensitivity to interferon (IFN) stimulation. Therefore, this study provides proof of principle for vector-free, targeted promoter demethylation in vivo.

Keywords:  Cxcl11; aerosol; demethylation; epigenetic editing; fusion demethylase; intra-airway; pulmonary; vector-free

DOI:  https://doi.org/10.1016/j.tibtech.2025.05.007
Aging Cell. 2025 Jul 02. e70084

Profiling Epigenetic Aging at Cell-Type Resolution Through Long-Read Sequencing.

Alec Eames, Mahdi Moqri, Jesse R Poganik, Vadim N Gladyshev.

  DNA methylation can give rise to robust biomarkers of aging, yet most studies profile it at the bulk tissue level, which masks cell type-specific alterations that may follow distinct aging trajectories. Long-read sequencing technology enables methylation profiling of extended DNA fragments, enabling mapping to their cell type of origin. In this study, we introduce a framework for evaluating cell type-specific aging using long-read sequencing data, without the need for cell sorting. Leveraging cell type-specific methylation patterns, we map long-read fragments to individual cell types and generate cell type-specific methylation profiles, which are used as input to a newly developed probabilistic aging model, LongReadAge, capable of predicting epigenetic age at the cell type level. We use LongReadAge to track aging of myeloid cells and lymphocytes from bulk leukocyte data as well as circulating cell-free DNA, demonstrating robust performance in predicting age despite limited shared features across samples. This approach provides a novel method for profiling the dynamics of epigenetic aging at cell type resolution.

Keywords:  aging; epigenetics; long‐read sequencing

DOI:  https://doi.org/10.1111/acel.70084