bims-caglex 2025-06-08 papers

bims-caglex

Biomed News

on Cellular aging and life extension

Issue of 2025–06–08
eighteen papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño

Longevity cosmeceuticals as the next frontier in cosmetic innovation: a scientific framework for substantiating product claims.
Dehydroacteoside rejuvenates senescence via TVP23C-CDRT4 regulation.
Glucagon receptor signaling is indispensable for the healthspan effects of caloric restriction in aging male mice.
Metformin: An Old Drug with New Tricks-Promising Role in Vascular Aging and Cardioprotection.
Creatine and cellular senescence: from molecular pathways to populational health.
Preventing MSC aging and enhancing immunomodulation: Novel strategies for cell-based therapies.
Taurine Alleviates Pancreatic β-Cell Senescence by Inhibition of p53 Pathway.
Short-Term DMOG treatment rejuvenates senescent mesenchymal stem cells by enhancing mitochondrial function and mitophagy through the HIF-1α/BNIP3 pathway.
Molecular mechanisms regulating PDE11A4 age-related liquid-liquid phase separation (LLPS) and its reversal by selective, potent and orally-available PDE11A4 small molecule inhibitors both in vitro and in vivo.
A Standardized Protocol for Mouse Longevity Studies in Preclinical Drug Development.
Safety and efficacy of platelet-rich plasma in the treatment of periorbital skin photoaging.
DNA Nano-Biomaterials Based Futuristic Technologies for Tissue Engineering and Regenerative Therapeutics.
Estrogen-related receptor alpha promotes skeletal muscle regeneration and mitigates muscular dystrophy.
Senescence and inflammation are unintended adverse consequences of CRISPR-Cas9/AAV6-mediated gene editing in hematopoietic stem cells.
An NF-kB/TNF-alpha signalling feedback loop acts to coordinate tissue regeneration and macrophage behaviour in zebrafish.
A Novel GH Deficient Rat Model Reveals Cross-Species Insights Into Aging.
Stem cell therapy for Parkinson's disease: A new hope for neural regeneration.
Development of an enhanced liver scaffold recellularization using fibronectin.

Front Aging. 2025 ;6 1586999

Longevity cosmeceuticals as the next frontier in cosmetic innovation: a scientific framework for substantiating product claims.

Wannita Klinngam, Athit Chaiwichien, Supawadee Osotprasit, Uracha Ruktanonchai, Mayuree Kanlayavattanakul, Nattaya Lourith, Amaraporn Wongrakpanich, Veerawat Teeranachaideekul, Tawin Iempridee.

  The field of anti-aging research has made remarkable strides with the identification of geroprotectors-compounds capable of extending healthspan and lifespan in animal models-presenting promising implications for human longevity. Building on these advances, we propose a novel product category: longevity cosmeceutical actives and products. Unlike conventional anti-aging products that primarily target superficial signs of aging, longevity cosmeceuticals address the molecular hallmarks of aging, fundamentally enhancing skin health and longevity. To clearly distinguish these scientifically validated products from marketing-driven claims, we define, for the first time, longevity cosmeceutical actives and products based on stringent criteria: (1) they must directly target and modulate established hallmarks of skin aging; (2) they must demonstrably extend "skinspan" over time, reflected by improved skin viability, structure, and functional integrity; and (3) their efficacy must be validated through clinical trials, preferably with post-trial skin biopsies to evaluate aging hallmark biomarkers, along with comprehensive safety assessments. This review explores molecular hallmarks of skin aging, highlights geroprotective compounds with potential cosmeceutical applications, and recommends essential biomarkers for assessing prevention of rapid biological aging. Additionally, we propose methodologies for skinspan assessment and emphasize the importance of robust clinical trial designs. By establishing these scientifically rigorous standards, we aim to drive innovation, substantiate longevity claims, and transform the cosmetic industry toward meaningful biological improvements in skin health.

Keywords:  aging hallmarks; geroprotectors; longevity cosmeceuticals; skin aging biomarkers; skinspan

DOI:  https://doi.org/10.3389/fragi.2025.1586999
Exp Gerontol. 2025 Jun 03. pii: S0531-5565(25)00129-9. [Epub ahead of print]207 112800

Dehydroacteoside rejuvenates senescence via TVP23C-CDRT4 regulation.

Yoo Jin Lee, Eun Seon Song, Yun Haeng Lee, Kyeong Seon Lee, Byeonghyeon So, Ji Ho Park, Jee Hee Yoon, Duyeol Kim, Minseon Kim, Hyung Wook Kwon, Youngjoo Byun, Ki Yong Lee, Joon Tae Park.

  One of the major factors inducing senescence is reactive oxygen species (ROS) produced from dysfunctional mitochondria. Therapeutic strategies that reduce mitochondrial ROS generation are considered essential for rejuvenating senescence, but effective methods have not yet been established. Here, we screened phenylpropanoids (PPs), secondary metabolites produced in response to oxidative stress in plants, and identified dehydroacteoside as a potential candidate. Dehydroacteoside restored mitochondrial function, thereby reducing mitochondrial ROS generated by inefficient electron transport. Furthermore, senescence-associated phenotypes were restored by dehydroacteoside-mediated ROS reduction. Using RNA sequencing, we identified TVP23C-CDRT4 as a gene that plays a critical role in dehydroacteoside-mediated senescence rejuvenation. Knockdown of TVP23C-CDRT4 showed similar effects to dehydroacteoside, reducing ROS and subsequently restoring senescence-associated phenotypes. Taken together, our study uncovered a novel mechanism by which dehydroacteoside reduces mitochondrial ROS generation, thereby restoring senescence. Our findings open the way to a new field of anti-aging therapy aimed at controlling senescence by modulating ROS production in mitochondria.

Keywords:  Dehydroacteoside; Reactive oxygen species; Senescence rejuvenation; TVP23C-CDRT4

DOI:  https://doi.org/10.1016/j.exger.2025.112800
bioRxiv. 2025 May 17. pii: 2025.05.13.653849. [Epub ahead of print]

Glucagon receptor signaling is indispensable for the healthspan effects of caloric restriction in aging male mice.

Kassandra R Bruner, Isabella R Byington, Tyler J Marx, Anastasiia Vasileva, Temara Fletcher, Susma Ghimire, India J Zappia, Yashika Shaju, Janan Zeng, Hallie R Wachsmuth, Thadeus W Carlyon, David G Besselsen, Daniel J Drucker, Frank A Duca, Jennifer H Stern.

Obesity and type 2 diabetes mellitus accelerate aging, shortening the duration of healthspan. Conversely, chronic calorie restriction (CR) extends healthspan. Research aimed at understanding the mechanism by which CR slows aging has focused heavily on insulin and downstream signaling cascades. Glucagon, a hormone that counter-regulates insulin, is commonly affected by these same interventions. To investigate the role of glucagon in aging we used dietary manipulation, global and liver-specific glucagon receptor knockout, and pharmacological glucagon receptor activation. We found that globally eliminating glucagon receptor signaling (Gcgr KO) decreases median lifespan by 35% in lean mice. These lifespan shortening effects are more robust in diet-induced obese mice (54%). Extending these findings to metabolic health, we found that glucagon receptor signaling is indispensable to the metabolic response to chronic CR in young and aged mice. While CR decreased liver fat, serum triglyceride, and serum cholesterol in WT mice, these metabolic benefits were absent in Gcgr KO mice. In line with these observations, we found that critical nutrient sensing pathways known to improve aging are dysregulated in mice lacking glucagon receptor signaling at the liver (Gcgr hep-/- ). Liver-specific deletion of the glucagon receptor decreases hepatic AMP Kinase activation in aging mice, regardless of diet. Further, CR decreases hepatic mTOR activity in WT mice, but not in Gcgr hep-/- mice. Together, these findings propose that glucagon signaling plays a critical role in both normal aging and the lifespan and healthspan extension driven by caloric restriction.

DOI: https://doi.org/10.1101/2025.05.13.653849
Drugs Aging. 2025 Jun 05.

Metformin: An Old Drug with New Tricks-Promising Role in Vascular Aging and Cardioprotection.

Rooban Sivakumar, K A Arul Senghor, V M Vinodhini, Janardhanan S Kumar.

Metformin, traditionally promoted for its efficacy in diabetes, is increasingly appreciated for its geroprotective potential in the development of vascular aging, a key contributor to cardiovascular morbidity. This review aims at understanding the spectrum of mechanisms that govern the amelioration of degenerative processes associated with vascular aging by metformin. Central to this therapeutic promise is the activation of AMPK, which reduces metabolic dysregulation and hence slows vascular senescence. Oxidative stress has been identified as an important mechanism thought to be enhanced by metformin in the preservation of endothelial function and attenuation of arterial stiffening. Besides, metformin has lipid-lowering and antiinflammatory activity, which is critical for reducing arterial rigidity and the development of atherosclerotic plaque. In recent times, both clinical and preclinical studies revealed empirical data that confirmed the effectiveness of metformin in the improvement of endothelial function and the decreasing of arterial stiffness as a part of a reduction in the rates of cardiovascular events. The therapeutic action of the drug goes beyond glycemic control, rendering it a geroprotector potentially suitable for broader application in age-related vascular decline. In light of these findings, the clinical acceptance of metformin as an intervention in vascular aging should be possible and promising. Carefully monitored follow-up studies are needed to optimize dosing, delineate the broad biological effects, and verify long-term benefits, which will underpin metformin's role in the paradigm against age-associated vascular diseases.

DOI: https://doi.org/10.1007/s40266-025-01215-3
Exp Gerontol. 2025 May 31. pii: S0531-5565(25)00127-5. [Epub ahead of print]207 112798

Creatine and cellular senescence: from molecular pathways to populational health.

Sergej M Ostojic, Viktória Prémusz, Pongrác Ács.

  Emerging evidence suggests that creatine, a naturally occurring amino acid derivative and conditionally essential nutrient, may modulate cellular senescence through mechanisms such as enhancing cellular energy homeostasis, mitigating oxidative stress, and influencing key signaling pathways implicated in aging processes. This review critically evaluates the current body of research, highlights existing gaps in the mechanistic understanding, and emphasizes the importance of targeted studies to further delineate creatine's role in cellular senescence and age-associated dysfunctions. By integrating perspectives from molecular biology, gerontology, and applied physiology, this paper aims to advance the understanding of creatine-based strategies as potential interventions for promoting healthy aging and preventing senescence-associated conditions.

Keywords:  Antioxidant; Bioenergetics; Creatine; Inflammation; Sarcopenia; Senescence-associated secretory phenotype

DOI:  https://doi.org/10.1016/j.exger.2025.112798
Regen Ther. 2025 Jun;29 517-539

Preventing MSC aging and enhancing immunomodulation: Novel strategies for cell-based therapies.

Faranak Elmi, Fatemeh Soltanmohammadi, Tahura Fayeghi, Safar Farajnia, Effat Alizadeh.

  The efficacy of mesenchymal stem cells (MSCs) mediated regenerative therapies has been hindered by the senescence of them during long period cultures. Aged MSCs exhibit altered morphology, decreased stemmas, changed intercellular communication, and poor differentiation ability. Besides in physiological condition, upon transplantation of senescent MSCs, they are capable of activating both the innate and adaptive immune systems, playing a crucial role in preserving tissue homeostasis. Therefore, enhancing immunomodulation properties and preventing aging progress of MSCs to achieve successful future clinical applications seems necessary. This review delves into the current knowledge of the underlying cellular and molecular mechanisms that promote MSCs senescence as well as the developed approaches for reversing or preventing MSCs aging. These include pre-treatment of MSCs with various types of molecules to inhibit aging process and implementation of different types of three-dimensional culture systems. In addition, the recently developed strategies to improve immunomodulatory properties of MSCs have been discussed. By addressing the limitations of aged MSCs and augmenting their immunomodulation, these approaches offer a promising avenue for the future of cell therapy and provide valuable tools for maximizing the effectiveness of MSCs therapy in biomedical applications.

Keywords:  Aging; Cell therapy; Immunomodulation; Mesenchymal stem cells (MSCs)

DOI:  https://doi.org/10.1016/j.reth.2025.04.014
J Diabetes. 2025 Jun;17(6): e70100

Taurine Alleviates Pancreatic β-Cell Senescence by Inhibition of p53 Pathway.

Baomin Wang, Ziyan Wang, Yumei Yang, Melody Yuen Man Ho, Runyue Yang, Huizi Yang, Siyi Liu, Huige Lin, Kenneth King Yip Cheng, Xiaomu Li.

   BACKGROUND: Pancreatic β-cells function deteriorates during aging, leading to increased risk of type 2 diabetes. We and others previously demonstrated that p53 activation triggers β-cell senescence and dysfunction in aging, but how its activity is controlled remains incompletely understood. Metabolites are not only by-products of metabolic pathways but also function as messengers to regulate various biological pathways. Taurine, a non-proteinogenic amino acid derived from cysteine, has demonstrated anti-aging effects in multiple cell types and tissues. Nevertheless, its role in β-cell senescence remains unclear.
METHODS: Untargeted metabolomic analysis was used to determine differential metabolites in pancreatic islets of mice during aging. In vitro, β-cell lines MIN6 and INS-1E were treated with taurine and its transporter inhibitor, followed by measurement of senescence-related markers. Multiple experimental techniques, such as LC-MS/MS, co-immunoprecipitation, DARTS analysis, and LiP-MS, were used to study the mechanistic actions of taurine.
RESULTS: Untargeted metabolomic analysis showed that taurine and taurocholic acid were significantly upregulated in aged islets. Pretreatment with taurine inhibited naturally aging, chemically induced senescent and inflammatory program, oxidative stress, and defective insulin secretion in pancreatic β-cells. SLC6A6 transporter was required to mediate exogenous taurine uptake, and inhibition of SLC6A6 abolished the anti-senescent effects of taurine. Taurine bound with CKDN2AIP and inhibited its interaction with p53, thereby promoting p53 degradation and suppressing the p53-dependent senescent program.
CONCLUSION: Our findings suggest that increasing β-cell taurine uptake might be a feasible approach to preserve β-cell function by targeting the p53-dependent senescent response.

Keywords:  cellular senescence; p53; pancreatic β‐cells; taurine

DOI:  https://doi.org/10.1111/1753-0407.70100
Stem Cell Res Ther. 2025 Jun 02. 16(1): 274

Short-Term DMOG treatment rejuvenates senescent mesenchymal stem cells by enhancing mitochondrial function and mitophagy through the HIF-1α/BNIP3 pathway.

Jiaxin Wen, Lingxian Yi, Lei Chen, Jinhan Xu, Yanmin Zhang, Qiheng Cheng, Hangyu Ping, Huanyu Wang, Feng Shuang, Wei Chai, Tujun Weng.

   BACKGROUND: Mesenchymal stem cells (MSCs) have potential for treating degenerative and immune diseases, but their clinical efficacy is limited by senescence, characterized by mitochondrial dysfunction, impaired mitophagy, and metabolic imbalance. The goal of this study was to investigate the effects of dimethyloxalylglycine (DMOG), a hypoxia-mimetic agent that stabilizes hypoxia-inducible factor 1 alpha (HIF-1α), on rejuvenating senescent MSCs by enhancing mitochondrial function, mitophagy, and metabolic reprogramming.
METHODS: Two models of MSC senescence were established: oxidative stress-induced senescence using hydrogen peroxide and replicative senescence through serial passaging. Umbilical cord derived MSCs were treated with DMOG for 48 h under normoxic conditions. Mitochondrial function, mitophagy, and metabolism were assessed using assays that measured mitochondrial membrane potential, reactive oxygen species levels, ATP production, and mitophagy. Western blotting and real-time PCR were employed to analyze the expression changes of relevant molecules. RNA sequencing (RNA-seq) was performed to identify key genes and pathways regulated by DMOG. Additionally, to evaluate the therapeutic potential of rejuvenated MSCs, a co-culture system was established, where DMOG-treated senescent MSCs were co-cultured with IL-1β-treated chondrocytes.
RESULTS: DMOG treatment significantly reduced key senescence markers, including senescence-associated beta-galactosidase, p53, and p21, in both senescence models. DMOG treatment restored mitochondrial morphology and function, improving mitochondrial membrane potential, reducing mitochondrial reactive oxygen species, and enhancing ATP production. DMOG also promoted mitophagy, as evidenced by increased colocalization of mitochondria with lysosomes. RNA-seq analysis revealed that DMOG activated key pathways, including HIF-1 signaling, calcium signaling, and mitophagy-related gene (BNIP3 and BNIP3L). Notably, BNIP3 knockdown greatly abolished DMOG-induced mitophagy and its anti-senescence effects. Furthermore, DMOG treatment improved metabolic flexibility by enhancing both mitochondrial respiration and glycolysis in senescent MSCs. Moreover, DMOG-treated senescent MSCs partially restored their therapeutic efficacy in an osteoarthritis model by improving extracellular matrix regulation in IL-1β-stimulated chondrocytes.
CONCLUSIONS: Short-term DMOG treatment rejuvenates senescent MSCs by enhancing mitochondrial function, promoting mitophagy via HIF-1α/BNIP3, and improving metabolic reprogramming. DMOG-treated MSCs also showed enhanced therapeutic efficacy in co-culture with IL-1β-treated chondrocytes, suggesting its potential to improve MSC-based therapies in regenerative medicine.

Keywords:  BNIP3; HIF-1α; Hypoxia-Mimetic agent; Mesenchymal stem cells (MSCs); Mitophagy; Senescence

DOI:  https://doi.org/10.1186/s13287-025-04422-2
bioRxiv. 2025 May 21. pii: 2025.05.20.654583. [Epub ahead of print]

Molecular mechanisms regulating PDE11A4 age-related liquid-liquid phase separation (LLPS) and its reversal by selective, potent and orally-available PDE11A4 small molecule inhibitors both in vitro and in vivo.

E Amurrio, J Patel, M Danaher, L Elzaree, J L Fisher, H Greene, P Kargbo, P Kim, E Klimentova, S Lin, Y Liu, M Y Mehboob, S Abdallah, Y Temesgen, S Ul Mahmood, D P Rotella, M P Kelly.

PDE11A is a little-studied phosphodiesterase family that breaks down cAMP and cGMP, with the PDE11A4 isoform enriched in the memory-related hippocampus. Age-related increases in hippocampal PDE11A expression occur in human and rodents, causing age-related cognitive decline of social memories. Interestingly, this age-related increase triggers PDE11A4 liquid-liquid phase separation (LLPS), causing the enzyme to accumulate in the brain in filamentous structures termed "ghost axons". Here we sought to identify molecular mechanisms regulating PDE11A4 LLPS and therapeutic approaches capable of reversing it. PDE11A4 LLPS was reduced by phosphorylation of PDE11A4-S163 or-S239 and the D355A mutation that blocks the effect of cGMP binding the PDE11A4 GAF-A domain. PDE11A4 LLPS was increased by inhibiting kinases with staurosporine or stimulating packaging/repacking via the trans-Golgi network by overexpressing TGN38 or RhoB. 8 PDE11 inhibitors (MLG-122, MLG-185, MLG-199, SMQ-02-57, SMQ-03-30, SMQ-03-20, tadalafil, and BC11-38) across 3 scaffolds reverse overexpression-related PDE11A4 LLPS in HT22 mouse hippocampal neuronal cells. This effect of PDE11A4 inhibitors occurs within minutes, is reversed upon washout of lower but not higher concentrations, and occurs in part by reducing PDE11A4 homodimerization. PDE11A4 inhibitors also rescued exacerbated PDE11A4 LLPS triggered by aging-like S117D/S124D phosphomimic mutations, staurosporine, or TGN38/RhoB overexpression. In vivo, orally-administered 30mg/kg SMQ-03-20 reversed age-related increases in PDE11A4 ghost axons and neuroinflammation in old mice. Thus, PDE11A inhibitors that reverse age-related PDE11A4 LLPS in HT22 hippocampal cells also reduce PDE11A4 ghost axons and neuroinflammation in the aged mouse brain, indicating therapeutical potential.

DOI: https://doi.org/10.1101/2025.05.20.654583
Aging Dis. 2025 Jun 04.

A Standardized Protocol for Mouse Longevity Studies in Preclinical Drug Development.

Alex Zhavoronkov, Qian Wang, Yujie Liu, Wenbin Hou, Yuelei Shen, Dominika Wilczok, Kristen Fortney, Alex Aliper, Man Zhang, Feng Ren, Richard A Miller.

Although aging is increasingly recognized as a key factor in chronic disease management, preclinical drug development rarely incorporates direct assessments of lifespan. To date, no biotechnology company has conducted a full mouse lifespan study for a therapeutic agent prior to human clinical trials, despite widespread chronic use of many approved drugs. This oversight stems from a lack of standardized protocols for the incorporation of mouse lifespan studies, high costs, limited commercial incentives, and regulatory risks associated with long-term data. Here, we present a comprehensive and scalable protocol for conducting mouse longevity studies in the early stages of drug development. Being aware of monetary constraints in the drug discovery process, we propose a basic design for a longevity study on ~250 (176 males and 72 females) genetically heterogeneous mice (UM-HET3) per group, with survival curves as primary endpoint, and propose enhanced study design options only if budget allows. Our framework provides a standardized foundation for integrating longevity assessments into routine drug development, offering the potential to uncover long-term risks or benefits that traditional toxicology studies may overlook. Broad implementation of such protocols could support the development of safer and more effective therapeutics for chronic diseases, while opening new avenues for discovery of substances that could slow down the rate of aging, known as geroprotectors.

DOI: https://doi.org/10.14336/AD.2025.0508
J Cosmet Laser Ther. 2025 Jun 02. 1-7

Safety and efficacy of platelet-rich plasma in the treatment of periorbital skin photoaging.

Xin-Li, Lingling-Hu, Weimin-Song, Qian-Lu.

  Periorbital skin photoaging is a common cosmetic problem.Presently, conventional treatment methods cannot achieve satisfactory results. Periorbital skin aging may benefit from platelet-rich plasma (PRP) injection. However, there is little experimental evidence on the safety and efficacy of PRP in the treatment of periorbital skin photoaging. To examine the safety and efficacy of PRP injection in the treatment of periorbital skin photoaging, PRP was injected into the periorbital skin of 20 patients, and patient satisfaction was assessed at the first month (M1), the second month (M2), and the third month (M3) after treatment. Two experienced dermatologists independently evaluated the patient's skin before and after treatment according to internationally accepted guidelines. The objective indicators of skin hydration, melanin index, erythema index, skin brightness, transepidermal water loss (TEWL), skin elasticity, and skin thickness were measured. Some subjective indicators, including pigmentation around the eyes, suborbital wrinkles, and static crow's feet, were significantly improved. Some objective indicators, including skin brightness, skin thickness, and collagen strength, were also significantly improved. Eye bags and TEWL slightly improved, but the differences were not statistically significant. The overall patient satisfaction with the treatment was high, no serious complications were noted, and the recovery profile was favorable. PRP injection was safe and effective for the treatment of periorbital skin photoaging.

Keywords:  Periorbital skin photoaging; platelet-rich plasma (PRP) injection; safety and efficacy

DOI:  https://doi.org/10.1080/14764172.2025.2513380
Small. 2025 Jun 03. e2504361

DNA Nano-Biomaterials Based Futuristic Technologies for Tissue Engineering and Regenerative Therapeutics.

Krupa Kansara, Abdulkhalik Mansuri, Ashutosh Kumar, Dhiraj Bhatia.

  The ability to completely repair or regenerate injured tissues or organs and restore their functionality has long been a goal of humankind. The advancements in tissue engineering and regenerative medicine have made this conceivable. With the ability to precisely manipulate nanoscale architectures for designing biomaterials, DNA nanotechnology has emerged as a groundbreaking technique in tissue engineering and regenerative medicine. DNA-based nanostructures are well-suited for directing cellular interactions, delivering therapeutic drugs, and mimicking extracellular matrix components due to their exceptional biocompatibility, programmability, and molecular recognition capabilities. Recent developments have demonstrated that DNA nanodevices can be used to administer drugs and growth factors in a controlled manner, as well as to enhance cell adhesion, proliferation, and differentiation. Furthermore, their capacity to respond to biological stimuli enables dynamic and adaptable tissue regeneration techniques. This review highlights the latest advances in DNA nanotechnology for regenerative applications, its benefits over traditional biomaterials, and potential future pathways for clinical translation.

Keywords:  DNA nanotechnology; regenerative therapeutics; tissue engineering; translational biomaterials

DOI:  https://doi.org/10.1002/smll.202504361
bioRxiv. 2025 May 19. pii: 2025.05.15.654390. [Epub ahead of print]

Estrogen-related receptor alpha promotes skeletal muscle regeneration and mitigates muscular dystrophy.

Thi Thu Hao Nguyen, Ya Xiang Huang, Svitlana Poliakova, Citu Citu, Eira Mann, Danesh H Sopariwala, Zhongming Zhao, Ashok Kumar, Vihang A Narkar.

Skeletal muscle regeneration in chronic muscle diseases such as Duchenne Muscular Dystrophy (DMD) has remained clinically unsurmountable. Estrogen-related receptor alpha (ERRα) plays a critical role in adult skeletal muscle metabolism and exercise fitness. Whether ERRα activation can drive muscle regeneration and mitigation of dystrophy in DMD is not known. We have investigated ERRα signaling in pre-clinical models of acute muscle injury and DMD. ERRα is induced in differentiating C2C12 myoblast and regenerating muscle. ERRα silencing suppressed proliferation and differentiation in C2C12 myoblasts. RNA sequencing revealed that angiogenic factor and proliferation genes were downregulated by ERRα knockdown in proliferating cells, whereas oxidative mitochondrial and differentiation regulator genes were downregulated in differentiating cells. In accordance with in vitro findings, transgenic ERRα overexpression in rodent skeletal muscle stimulates muscle regeneration after acute BaCl 2 injury, which is accompanied by enhanced angiogenesis and mitochondrial biogenesis. Notably, ERRα and its angiogenic and metabolic target gene expression is suppressed in muscle stem cells (MuSCs) derived from dystrophic muscles in mdx mice, coinciding with proliferation and differentiation defect in these cells. Loss of ERRα and its target gene expression was recapitulated in adult dystrophic mdx muscles. Consequently, muscle specific ERRα overexpression in mdx mice restored angiogenic and metabolic gene expression, induced vascular and oxidative remodeling, alleviated baseline muscle damage, and boosted regeneration after BaCl2 injury in dystrophic muscle. Our studies demonstrate a pro-regenerative role of ERRα and its deficiency in dystrophic muscles and its MuSCs. ERRα restoration could be a therapeutic strategy for DMD through angio-metabolic gene program.

DOI: https://doi.org/10.1101/2025.05.15.654390
Cell Rep Med. 2025 May 30. pii: S2666-3791(25)00230-7. [Epub ahead of print] 102157

Senescence and inflammation are unintended adverse consequences of CRISPR-Cas9/AAV6-mediated gene editing in hematopoietic stem cells.

Anastasia Conti, Kety Giannetti, Federico Midena, Stefano Beretta, Nicolò Gualandi, Rosaria De Marco, Edoardo Carsana, Angelica Varesi, Teresa Tavella, Laura Alessandrini, Parinaz Zarghamian, Alessandra Weber, Samuele Ferrari, Chiara Brombin, Diego Gilioli, Lucrezia Della Volpe, Stephanie Z Xie, Ivan Merelli, Toni Cathomen, Luigi Naldini, Raffaella Di Micco.

  Gene editing (GE) using homology-directed repair (HDR) in hematopoietic stem and progenitor cells (HSPCs) offers promise for long-range gene correction of inherited genetic disorders. However, cellular responses induced by CRISPR-Cas9/AAV6 engineering impair the long-term repopulating potential of HDR-edited HSPCs, adversely impacting the safety and efficacy of clinical translation. Our study uncovers a durable senescence-like response in genetically engineered HSPCs triggered by p53 and interleukin (IL)-1/nuclear factor κB (NF-κB) activation, which restricts graft size and clonal diversity in long-term transplantation assays. We show that transient p53 inhibition or blocking inflammatory pathways mitigates senescence-associated responses, improving the repopulating capacity of edited HSPCs. Importantly, we identify treatment with Anakinra, an IL-1 signaling antagonist, as a promising strategy to enhance polyclonal output in HDR-edited cells while minimizing genotoxicity risks associated with the editing procedure. Overall, our findings present strategies to overcome key hurdles in HDR-based HSPC gene therapies, providing a framework for enhancing their efficacy and safety in clinical applications.

Keywords:  CRISPR-Cas9; DNA damage; gene editing; gene therapy; genome integrity; hematopoietic stem cells; inflammatory programs; p53; senescence; viral vectors

DOI:  https://doi.org/10.1016/j.xcrm.2025.102157
NPJ Regen Med. 2025 Jun 03. 10(1): 27

An NF-kB/TNF-alpha signalling feedback loop acts to coordinate tissue regeneration and macrophage behaviour in zebrafish.

Kalliopi Arkoudi, Yue Yuan, Antonia Pia Cumine, Carlene Dyer, Elisabeth Busch-Nentwich, Isabel Bravo, Yi Feng, Robert D Knight.

Inflammatory cells are crucial regulators of infection and regeneration that actively migrate to affected tissues. NF-kB and TNF-alpha (TNFα) are master regulators of immune signalling, but their importance for immune cell migration is much less well understood. We have therefore investigated how NF-kB and TNFα regulate both macrophage function and behaviour in vivo using a zebrafish model of tissue repair. We show that NF-kB activity differentially regulates TNFα activity through Tnf receptors 1a and 1b to control macrophage responses to injury. Loss of NF-kB in macrophages results in elevated TNFα expression and results in more directional migration. Impaired NF-kB activity in macrophages perturbs tissue regeneration, causes increased proliferation, altered pro- and anti-inflammatory gene expression and delays fin regeneration. We identify a crucial role for NF-kB modulation of TNFα signaling to regulate macrophage responses to tissue injury, which are necessary for effective fin regeneration.

DOI: https://doi.org/10.1038/s41536-025-00414-1
Aging Cell. 2025 Jun 05. e70126

A Novel GH Deficient Rat Model Reveals Cross-Species Insights Into Aging.

Soe Maung Maung Phone Myint, Alexander Tate Lasher, Kaimao Liu, Aron M Geurts, Steven N Austad, Liou Y Sun.

  Multiple studies in mice with genetically disrupted growth hormone (GH) signaling have demonstrated that such disruption results in reduced body size, robustly increased longevity (> 50% in some cases), and improvements across multiple health parameters. However, it remains unclear how generalizable these findings are across mammals. Evidence in rats is limited and inconsistent. These conflicting results highlight the need for further investigation into the role of GH signaling in longevity across species. To address this gap, we developed a novel GH-deficient rat model using CRISPR/Cas9 technology to introduce a 10 bp deletion in exon 3 of the gene encoding rat GH-releasing hormone (GHRH) yielding a non-functional GHRH product. Physiological characterization of GHRH knockout (KO) rats revealed that they were half the body weight of wild-type controls. Additionally, relative to controls, they displayed an increased percent body fat, enhanced insulin sensitivity, reduced circulating insulin-like growth factor I (IGF-I) concentration, and a decreased reliance on glucose oxidation for energy metabolism, as determined by indirect calorimetry. Analysis of the gut microbial community in adult GHRH-KO rats further revealed a less diverse male microbiome, but a more diverse female KO microbiome compared to controls. Collectively, these findings demonstrate that multiple aspects of the GH activity-deficient phenotype, well-documented in mice, are faithfully recapitulated in our rat model. Therefore, the GHRH-deficient rat model represents a valuable new tool for advancing our understanding of the role of GH signaling in aging processes.

Keywords:  aging; endocrinology; gender differences; insulin/IGF‐1 signaling; lifespan; longevity; metabolic rate; rat models

DOI:  https://doi.org/10.1111/acel.70126
World J Biol Chem. 2025 Jun 05. 16(2): 106850

Stem cell therapy for Parkinson's disease: A new hope for neural regeneration.

Yasmin Garkani Mokhtari, Irene Varnava, Kosmas Kyrgiannis, Vasiliki Ampatsidou, Dimitrios Giakoumettis.

  Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by the loss of dopaminergic neurons in the substantia nigra that leads to reduced dopamine levels and impaired motor function. Current treatments only provide temporary symptom relief without addressing the underlying neuronal loss. A promising new approach for treating PD is stem cell therapy, particularly induced pluripotent stem cells and human pluripotent stem cells. They have the ability to differentiate into various neural cells, offering potential for neuronal replacement and restoration of brain function. Induced pluripotent stem cells are derived from reprogramming adult cells and present advantages such as genetic compatibility and reduced immune rejection, overcoming ethical concerns associated with embryonic stem cells. Preclinical studies show promising results, demonstrating that stem cells can differentiate into dopaminergic neurons and improve motor function in animal models. These advancements pave the way for clinical trials and potential long-term solutions for patients with PD. This review highlighted the significance of stem cell therapy in neuroregeneration and addressed preclinical successes, challenges in long-term safety, and ethical considerations, with the hope of revolutionizing PD treatment and improving patient outcomes.

Keywords:  Adult stem cells; Human pluripotent stem cells; Induced pluripotent stem cells; Parkinson’s disease; Stem cells

DOI:  https://doi.org/10.4331/wjbc.v16.i2.106850
J Biomater Appl. 2025 Jun 05. 8853282251350315

Development of an enhanced liver scaffold recellularization using fibronectin.

Sadia Afrin, Usha Yadav, Chandra J Yadav, Jihad Kamel, Jun-Young Lee, Kyung-Mee Park.

  Decellularized liver scaffolds offer a promising foundation for liver tissue engineering and regenerative medicine. However, several challenges such as poor cell adhesion, inefficient reseeding, inadequate vascularization, and a high risk of blood clot formation continue to hinder their clinical application. While fibronectin (FN) has been widely used to enhance scaffold functionality, its potential for liver-specific applications remains largely unexplored. In this study, we developed a perfusion-assisted FN coating technique to improve the adhesion of endothelial cells (EA.hy926) and hepatocytes (HepG2), thereby enhancing the overall biocompatibility of liver scaffolds. FN was carefully introduced into decellularized rat liver scaffolds, allowing for targeted deposition across both the vascular and parenchymal compartments to optimize cellular attachment. Following portal vein reseeding and 7 days of bioreactor incubation, the FN-coated scaffolds showed significantly better endothelial cell adhesion within blood vessel structures and increased HepG2 cell coverage throughout the liver tissue. Immunohistochemistry (IHC) confirmed enhanced HepG2 proliferation, while TUNEL and RT-qPCR analyses indicated improved cell viability and scaffold functionality. Additionally, ex vivo blood perfusion tests demonstrated reduced thrombogenicity, likely due to improved endothelialization and lower platelet adhesion. These findings highlight FN functionalization as an effective bioengineering approach to overcoming key barriers in vascularization, biocompatibility, and cellular integration for liver scaffolds. By extending the known benefits of FN beyond its previously studied applications in kidney and heart scaffolds, this research introduces a promising strategy for advancing bioengineered liver grafts and potential transplantation models.

Keywords:  Decellularization; fibronectin; liver; recellularization; scaffold

DOI:  https://doi.org/10.1177/08853282251350315