bims-caglex 2025-02-23 papers

bims-caglex

Biomed News

on Cellular aging and life extension

Issue of 2025–02–23
28 papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño

[Multi-Omic Rejuvenation: A New Strategy for Lifespan Extension].
Taurine and Berberine: Nutritional Interventions Targeting Cellular Mechanisms of Aging and Longevity.
Cordycepin extends the longevity of Caenorhabditis elegans via antioxidation and regulation of fatty acid metabolism.
Glibenclamide targets MDH2 to relieve aging phenotypes through metabolism-regulated epigenetic modification.
AI-Driven Robotics Laboratory Identifies Pharmacological TNIK Inhibition as a Potent Senomorphic Agent.
The Role of Hypoxia in Longevity.
Fasting the Stem Cells to Boost their Metabolic Functions.
Targeting Mitochondrial Integrity as a New Senolytic Strategy.
Senolytic elimination of senescent cells improved periodontal ligament stem cell-based bone regeneration partially through inhibiting YAP.
Regulatory Roles of Exosomes in Aging and Aging-Related Diseases.
Enhanced paracrine action of FGF21 in stromal cells delays thymic aging.
The Role of Ginseng and its Bioactive Compounds in Aging: Cells and Animal Studies.
Centella asiatica improves sleep quality and quantity in aged mice.
Engineered heart muscle reinvigorates failing hearts.
Characterization of senescence and nuclear reorganization in aging gingival cells.
Cellular senescence: from homeostasis to pathological implications and therapeutic strategies.
Regulatory Network Inference of Induced Senescent Midbrain Cell Types Reveals Cell Type-Specific Senescence-Associated Transcriptional Regulators.
Activity-based sensing reveals elevated labile copper promotes liver aging via hepatic ALDH1A1 depletion.
Quiescence modulates age-related changes in the functional capacity of highly proliferative canine lung mesenchymal stromal cell populations.
Liposome-Enabled Nanomaterials for Muscle Regeneration.
Context-specific interaction of the lipid regulator DIP-2 with phospholipid synthesis in axon regeneration and maintenance.
Persisting blood-brain barrier disruption following cisplatin treatment in a mouse model of chemotherapy-associated cognitive impairment.
The mechanism of perilla oil in regulating lipid metabolism.
Targeted ErbB4 receptor activation prevents D-galactose-induced neuronal senescence via inhibiting ferroptosis pathway.
Correction to "Bats as instructive animal models for studying longevity and aging".
Multi-tissue transcriptomic aging atlas reveals predictive aging biomarkers in the killifish.
[Geroprotective Properties of the ATM Inhibitor KU-60019 in Three Drosophila Species Differing in Lifespan].
Altered relaxation and Mitochondria-Endoplasmic Reticulum Contacts Precede Major (Mal)adaptations in Aging Skeletal Muscle and are Prevented by Exercise.

Mol Biol (Mosk). 2024 Sep-Oct;58(5):58(5): 684-693

[Multi-Omic Rejuvenation: A New Strategy for Lifespan Extension].

O Y Rybina, E G Pasyukova.

  Various age-related disorders accumulate during aging, causing a decline in tissue and organ function, raising the risk of disease development, and leading to death. Age-related phenotypes are tightly related to an increase in coordinated, progressive changes in the transcriptome, proteome, metabolome, microbiome, and epigenome. Age-dependent modifications of the transcriptome, caused by changes in epigenetic, transcriptional, and post-transcriptional regulation of gene expression, lead to the accumulation of age-related changes in the proteome and metabolome. In turn, dynamic changes in the microbiota during aging also affect gene expression and thus lead to age-related changes in the proteome and metabolome. Recent studies have shown that multi-omic rejuvenation technologies decrease age-related disorders and extend longevity. For example, the short-term induction of the expression of transcription factors that ensure the reprogramming of somatic cells into pluripotent stem cells is accompanied by the restoration of the DNA methylation pattern and transcriptome expression profile characteristic of younger tissues, resulting in an increased lifespan. In this review, we discuss existing multi-omic rejuvenation technologies and the prospects for extending and improving life.

Keywords:  aging; epigenome; lifespan; metabolome; microbiome; multi-omic technologies; proteome; transcriptome

DOI:  https://doi.org/10.31857/S0026898424050013, EDN: HUVYAW
Cardiol Rev. 2025 Feb 19.

Taurine and Berberine: Nutritional Interventions Targeting Cellular Mechanisms of Aging and Longevity.

Jatin Thukral, Pyush Moudgil, Darshilkumar Maheta, Siddharth Pravin Agrawal, Harbir Kaur, Nikhil Thukral, William H Frishman, Wilbert S Aronow.

Aging is a multifaceted biological process characterized by progressive physiological decline and increased susceptibility to diseases. Central to this process are molecular and cellular changes that contribute to hallmark features of aging, including mitochondrial dysfunction, genomic instability, telomere attrition, and cellular senescence. Emerging research highlights the role of nutrient deficiencies in accelerating aging, bringing dietary supplements such as taurine and berberine into focus. Taurine, a sulfur-containing amino acid, plays a critical role in cellular protection, osmoregulation, and antioxidant defense, with evidence linking its deficiency to cellular senescence, mitochondrial dysfunction, and stem cell exhaustion. Berberine, an isoquinoline alkaloid, exerts antiaging effects by modulating key signaling pathways, including adenosine monophosphate-activated protein kinase/mechanistic target of rapamycin and sirtuin 1, and promoting mitohormesis. This review explores the mechanisms by which taurine and berberine mitigate aging processes, highlighting their effects on cellular metabolism, stress response, and longevity. Animal studies demonstrate their potential to enhance health span and lifespan although human clinical trials remain limited. Future research should focus on elucidating their molecular pathways, evaluating their combined effects with other interventions such as caloric restriction, and optimizing dosage for clinical applications. Taurine and berberine represent promising therapeutic candidates for addressing fundamental aspects of aging and advancing strategies for healthy aging and lifespan extension.

DOI: https://doi.org/10.1097/CRD.0000000000000885
Eur J Pharmacol. 2025 Feb 17. pii: S0014-2999(25)00142-6. [Epub ahead of print]994 177388

Cordycepin extends the longevity of Caenorhabditis elegans via antioxidation and regulation of fatty acid metabolism.

Yang Sun, Mengling Zhong, Jingjie Wang, Mingmei Feng, Caihong Shen, Zhipeng Han, Xiaonian Cao, Qi Zhang.

  Aging can cause age-related diseases such as cancer, cardiovascular and neurodegenerative diseases. Cordycepin exerts anti-oxidation, anti-inflammatory and neuroprotective effects. However, the anti-aging effect of cordycepin is still unclear. This study aimed to investigate the anti-aging effect of cordycepin and unravel the underlying mechanism. Cordycepin prolonged the lifespan of C. elegans under normal and heat stress conditions, without effects on the normal growth and reproduction of C. elegans. Cordycepin also improved the locomotion ability, inhibited the deposition of aging pigment lipofuscin and alleviated the oxidative stress damage by decreasing the excessive accumulation of ROS and raising the antioxidant enzyme activities in C. elegans. The metabolomics study showed that cordycepin changed 19 metabolites including citric acid, linoleic acid, oleic acid, glutamic acid, pyruvic acid and so on. Transcriptomics study revealed that cordycepin up-regulated the gene expression of acox-1.2, acox-1.3, acox-1.4, acs-1, acs-15, acdh-1, acdh-4 and acdh-8 in C. elegans, suggesting that cordycepin prolonged its lifespan via regulating fatty acid degradation, fatty acid metabolism and so on. In summary, the current study demonstrated that cordycepin exerted the anti-aging effect on C. elegans by improving the antioxidant system and regulating the genes involved in fatty acid metabolism to inhibit the accumulation of linoleic acid and oleic acid. Therefore, cordycepin might be a promising agent for aging and age-related diseases.

Keywords:  Aging; Antioxidation; Caenorhabditis elegans; Cordycepin; Fatty acid metabolism

DOI:  https://doi.org/10.1016/j.ejphar.2025.177388
Signal Transduct Target Ther. 2025 Feb 17. 10(1): 67

Glibenclamide targets MDH2 to relieve aging phenotypes through metabolism-regulated epigenetic modification.

Zhifan Mao, Wenwen Liu, Rong Zou, Ling Sun, Shuman Huang, Lingyu Wu, Liru Chen, Jiale Wu, Shijie Lu, Zhouzhi Song, Xie Li, Yunyuan Huang, Yong Rao, Yi-You Huang, Baoli Li, Zelan Hu, Jian Li.

Mitochondrial metabolism-regulated epigenetic modification is a driving force of aging and a promising target for therapeutic intervention. Mitochondrial malate dehydrogenase (MDH2), an enzyme in the TCA cycle, was identified as an anti-aging target through activity-based protein profiling in present study. The expression level of MDH2 was positively correlated with the cellular senescence in Mdh2 knockdown or overexpression fibroblasts. Glibenclamide (Gli), a classic anti-glycemic drug, was found to inhibit the activity of MDH2 and relieve fibroblast senescence in an MDH2-dependent manner. The anti-aging effects of Gli were also further validated in vivo, as it extended the lifespan and reduced the frailty index of naturally aged mice. Liver specific Mdh2 knockdown eliminated Gli's beneficial effects in naturally aged mice, reducing p16INK4a expression and hepatic fibrosis. Mechanistically, MDH2 inhibition or knockdown disrupted central carbon metabolism, then enhanced the methionine cycle flux, and subsequently promoted histone methylation. Notably, the tri-methylation of H3K27, identified as a crucial methylation site in reversing cellular senescence, was significantly elevated in hepatic tissues of naturally aged mice with Mdh2 knockdown. Taken together, these findings reveal that MDH2 inhibition or knockdown delays the aging process through metabolic-epigenetic regulation. Our research not only identified MDH2 as a potential therapeutic target and Gli as a lead compound for anti-aging drug development, but also shed light on the intricate interplay of metabolism and epigenetic modifications in aging.

DOI: https://doi.org/10.1038/s41392-025-02157-3
Aging Dis. 2025 Feb 17.

AI-Driven Robotics Laboratory Identifies Pharmacological TNIK Inhibition as a Potent Senomorphic Agent.

Qiuqiong Tang, Deyong Xiao, Alexander Veviorskiy, Ying Xin, Sarah W Y Lok, Fadi E Pulous, Peiran Zhang, Yunfeng Zhu, Yongming Ma, Xiao Hu, Shoulai Gu, Chenting Zong, Sabina Mukba, Mikhail Korzinkin, Frank W Pun, Man Zhang, Alex Aliper, Lijuan Wu, Feng Ren, Li Zhang, Alex Zhavoronkov.

Assessing impact on the hallmarks of aging has emerged as a novel method for prioritizing dual-purpose longevity therapeutic targets and developing drugs simultaneously targeting aging and disease. Cellular senescence, a central hallmark of aging, progressively induces cellular growth arrest and accelerates the production of a pro-inflammatory senescence-associated secretory phenotype (SASP). TGF-β signaling is situated at the center of multiple senescence-associated and aging-associated signaling pathways, and its inhibition may be favorable for aging-related disorders. A recently developed Traf2- and Nck-interacting kinase (TNIK) inhibitor, INS018_055, was identified as a potent, novel anti-fibrotic agent affecting multiple hallmarks of aging across fibrotic diseases. Thus, we hypothesized that TNIK is a potential senescence modulator and INS018_055 could attenuate senescent cell accumulation to treat specific age-related pathological processes. Using a fully automated robotics laboratory designed for automated, highly parallel, and iterative phenotypic and multi-omic analyses, we determined that pharmacological or siRNA-mediated TNIK inhibition decreased cellular senescence in multiple experimental senescence models. INS018_055 mechanistically demonstrated senomorphic activity through its reduction of SASP. Furthermore, transcriptomics analysis revealed that INS018_055 treatment reduced aging signatures and extracellular matrix fibronectin through TGF-β signaling. These findings reveal TNIK's previously unappreciated role in cellular senescence and INS018_055's senomorphic potential in mitigating processes well-established as driving organismal aging. Thus, TNIK inhibition as a novel senomorphic strategy may inform future therapeutic approaches for diverse aging-related diseases.

DOI: https://doi.org/10.14336/AD.2024.1492
Aging Dis. 2025 Feb 17.

The Role of Hypoxia in Longevity.

Ayesha Nisar, Sawar Khan, Yongzhang Pan, Li Hu, Pengyun Yang, Naheemat Modupeola Gold, Zhen Zhou, Shengjie Yuan, Meiting Zi, Sardar Azhar Mehmood, Yonghan He.

Aging is marked by a progressive decrease in physiological function and reserve capacity, which results in increased susceptibility to diseases. Understanding the mechanisms of driving aging is crucial for extending health span and promoting human longevity. Hypoxia, marked by reduced oxygen availability, has emerged as a promising area of study within aging research. This review explores recent findings on the potential of oxygen restriction to promote healthy aging and extend lifespan. While the role of hypoxia-inducible factor 1 (HIF-1) in cellular responses to hypoxia is well-established, its impact on lifespan remains complex and context-dependent. Investigations in invertebrate models suggest a role for HIF-1 in longevity, while evidence in mammalian models is limited. Hypoxia extends the lifespan independent of dietary restriction (DR), a known intervention underlying longevity. However, both hypoxia and DR converge on common downstream effectors, such as forkhead box O (FOXO) and flavin-containing monooxygenase (FMOs) to modulate the lifespan. Further work is required to elucidate the molecular mechanisms underlying hypoxia-induced longevity and optimize clinical applications. Understanding the crosstalk between HIF-1 and other longevity-associated pathways is crucial for developing interventions to enhance lifespan and healthspan. Future studies may uncover novel therapeutic strategies to promote healthy aging and longevity in human populations.

DOI: https://doi.org/10.14336/AD.2024.1630
Curr Stem Cell Res Ther. 2025 Feb 18.

Fasting the Stem Cells to Boost their Metabolic Functions.

Pedro Henrique Maglio França, Giovanna Rosa Degasperi.

  Tissue homeostasis and regeneration depend on differentiated stem cells into specialized cell types. Dietary interventions, such as caloric restriction, are critical regulators of stem cell functions by altering their metabolism. This review discusses recent studies illustrating how diet interventions impact stem cell function. We summarize molecular targets and physiological effects of different types of caloric restriction and ketogenic mimicking diets in stem cells from bone marrow, muscle, and intestine. Furthermore, we highlight the nutrient-sensing pathway target of stem cells during caloric restriction. Understanding how nutrient signaling controls stem cell fate decisions is important to developing dietary interventions to improve the clinical application of stem cells.

Keywords:  Dietary interventions; caloric restriction; fasting; ketogenic diet; mTORC.; metabolism; stem cells

DOI:  https://doi.org/10.2174/011574888X340501250210042712
Aging Dis. 2025 Feb 08.

Targeting Mitochondrial Integrity as a New Senolytic Strategy.

Eliska Vacurova, Edita Vlachova, Jan Stursa, Klara Bohacova, Tereza Havrlantova, Vojtech Skop, Barbora Judita Kasperova, Lukas Werner, Jiri Neuzil, Martin Haluzik, Sona Stemberkova Hubackova.

Aging, characterized by accumulation of senescent cells, is a driving factor of various age-related diseases. These conditions pose significant health risks globally due to their increasing prevalence and serious complications. Reduction of senescent cells therefore represents a promising strategy promoting healthy aging. Here we demonstrate that targeting tamoxifen to mitochondria via triphenyl and tricyclohexyl phosphine selectively eliminates senescent cells. Our findings show a complex effect of mitochondrially targeted tamoxifen on mitochondrial function and integrity of senescent cells, including inhibition of oxidative phosphorylation and activity of respiratory complex IV. These changes result in activation of ferroptosis as the major mode of cell death, which results in rejuvenation of tissues. Targeting mitochondria of senescent cells represents a general senolytic strategy and may extend the healthspan and improve the quality of life in aging populations.

DOI: https://doi.org/10.14336/AD.2024.1100
Biochim Biophys Acta Mol Cell Res. 2025 Feb 17. pii: S0167-4889(25)00026-6. [Epub ahead of print]1872(3): 119921

Senolytic elimination of senescent cells improved periodontal ligament stem cell-based bone regeneration partially through inhibiting YAP.

Linglu Jia, Han Xiao, Zhenghao Hao, Shaoqing Sun, Wenxi Zhao, Zikai Gong, Weiting Gu, Yong Wen.

  Periodontal ligament stem cell (PDLSC)-based tissue engineering is an important method to promote periodontal tissue regeneration. However, PDLSCs are susceptible to the effects of replicative senescence, leading to reduced proliferation and differentiation abilities and weakened tissue regeneration potential. Senolytics (the combination of dasatinib and quercetin) are drugs that inhibit cellular aging through inducing the apoptosis of senescent cells, but whether they have positive effects during the senescence of PDLSCs is unknown. The present study established a long-term in vitro culture model of PDLSCs and then analyzed the effects of senolytics on the senescence, apoptosis, and osteogenic differentiation of PDLSCs in vitro and PDLSC-based tissue regeneration in vivo. The results showed that senolytics delayed the process of aging in prolonged-cultured PDLSCs and promoted the elimination and apoptosis of senescent cells. Moreover, senolytics improved the osteogenic differentiation ability of both young and senescent PDLSCs in vitro and promoted PDLSC-based alveolar bone regeneration in vivo. Furthermore, senolytics inhibited the expression of YAP in senescent PDLSCs. Their antiaging effects were enhanced when combined with the YAP inhibitor verteporfin, but were inhibited when combined with the YAP activator NIBR-LTSi. Taken together, these findings suggest that senolytics promoted the elimination of senescent PDLSCs and enhanced senescent PDLSC-based bone regeneration, partially through the inhibition of YAP expression.

Keywords:  Cellular senescence; Dasatinib; Quercetin; Senolytics; Stem cells; YAP

DOI:  https://doi.org/10.1016/j.bbamcr.2025.119921
Biogerontology. 2025 Feb 18. 26(2): 61

Regulatory Roles of Exosomes in Aging and Aging-Related Diseases.

Nanyin Xiao, Qiao Li, Guangyu Liang, Zonghao Qian, Yan Lin, Heng Zhang, Yangguang Fu, Xiao Yang, Cun-Tai Zhang, Jiankun Yang, Anding Liu.

  Exosomes are small vesicles with diameters ranging from 30 to 150 nm. They originate from cellular endocytic systems. These vesicles contain a rich payload of biomolecules, including proteins, nucleic acids, lipids, and metabolic products. Exosomes mediate intercellular communication and are key regulators of a diverse array of biological processes, such as oxidative stress and chronic inflammation. Furthermore, exosomes have been implicated in the pathogenesis of infectious diseases, autoimmune disorders, and cancer. Aging is closely associated with the onset and progression of numerous diseases and is significantly influenced by exosomes. Recent studies have consistently highlighted the important functions of exosomes in the regulation of cellular senescence. Additionally, research has explored their potential to delay aging, such as the alleviatory effects of stem cell-derived exosomes on the aging process, which offers broad potential for the development and application of exosomes as anti-aging therapeutic strategies. This review aims to comprehensively investigate the multifaceted impact of exosomes while concurrently evaluating their potential applications and underscoring their strategic significance in advancing anti-aging strategies.

Keywords:  Age-related diseases; Aging; Cellular senescence; Exosome; SASP

DOI:  https://doi.org/10.1007/s10522-025-10200-7
Nat Aging. 2025 Feb 19.

Enhanced paracrine action of FGF21 in stromal cells delays thymic aging.

Yun-Hee Youm, Christy Gliniak, Yuan Zhang, Tamara Dlugos, Philipp E Scherer, Vishwa Deep Dixit.

Age-related thymic involution precedes aging of all other organs in vertebrates and initiates the process of declining T cell diversity, which leads to eventual immune dysfunction. Whether FGF21, a liver-derived pro-longevity hormone that is also produced in thymic stroma, including by adipocytes, controls the mechanism of thymic demise is incompletely understood. Here, we demonstrate that elevation of FGF21 in thymic epithelial cells (TECs) and in adipocytes protects against thymic aging, whereas conditional hepatic overexpression did not impact thymic biology in aged mice. Notably, elevation of thymic FGF21 increased naïve CD8 T cells in aged animals and extended healthspan. Mechanistically, thymic FGF21 overexpression elevated TECs and reduced fibroadipogenic cells. Ablation of β-klotho, the obligatory co-receptor for FGF21 in Foxn1+ TECs, accelerated thymic aging, suggesting regulation of TECs by FGF21 is partially required for thymic lymphopoiesis. These findings establish that paracrine FGF21 improves thymic function and delays immune aging.

DOI: https://doi.org/10.1038/s43587-025-00813-5
Annu Rev Food Sci Technol. 2025 Feb 19.

The Role of Ginseng and its Bioactive Compounds in Aging: Cells and Animal Studies.

Da-Yeon Lee, Nicole Noren Hooten, Jennifer F O'Connell, Boo-Yong Lee, Yoo Kim.

Aging is an inevitable process that is characterized by physiological deterioration and increased vulnerability to stressors. Therefore, the interest in hallmarks, mechanisms, and ways to delay or prevent aging has grown for decades. Natural plant products and their bioactive compounds have been studied as a promising strategy to overcome aging. Ginseng, a traditional herbal medicine, and its bioactive compound, the ginsenosides, have increasingly gained attention because of various pharmacological functions. This review introduces the species, useful parts, characteristics, and active components of ginseng. It primarily focuses on the bioconversion of ginsenosides through the unique steaming and drying process. More importantly, this review enumerates the antiaging mechanisms of ginseng, ginsenosides, and other bioactive compounds, highlighting their potential to extend the health span and mitigate age-related diseases based on twelve representative hallmarks of aging.

DOI: https://doi.org/10.1146/annurev-food-111523-121753
bioRxiv. 2025 Feb 06. pii: 2025.02.01.636070. [Epub ahead of print]

Centella asiatica improves sleep quality and quantity in aged mice.

Laura Dovek, Carolyn E Tinsley, Katelyn Gutowsky, Kayla McDaniel, Zoe Potter, Matthias Ruffins, Noah E P Milman, Claire Wong, Amala Soumyanath, Nora E Gray, Miranda M Lim.

Age-related sleep disruption is common in older adults. Not only does the total amount of time spent in sleep decline, but the number of arousals during sleep increases with age. As sleep is important for both memory consolidation and to prevent neurodegenerative pathology, this decline in sleep and/or sleep consolidation may underlie age-related cognitive decline and dementias. Furthermore, treatment of sleep disruption can improve quality of life. However, few interventions have successfully reversed age-related sleep decline. Extracts from the plant Centella asiatica have demonstrated neuroprotective effects in human, rodent, and fly models of aging and neurodegenerative diseases, and is a promising intervention for dementias, yet little is known about how these extracts affect sleep patterns. Here, we administered Centella asiatica water extract ( CAW) dosed or control chow to male and female C57BL6/J mice aged 18 months. Effects on sleep composition were determined using electrodes that recorded EEG and EMG signals. We found that CAW dosed chow (1000 mg/kg/day) increased REM sleep time in aged male mice and decreased the number of arousals during sleep observed in aged females, compared to age- and sex-matched controls. We conclude that CAW administered in food has a moderate, sex-dependent effect on sleep quantity and quality.
Statement of Significance: Sleep declines with age and may underline age-related cognitive changes. However, few interventions have successfully reversed age-related sleep and cognitive decline. This study found that botanical extract from the plant Centella asiatica increased total REM sleep time in aged male mice, and decreased sleep fragmentation in aged female mice, compared to age- and sex-matched controls. Whether these moderate, sex-dependent effect sizes on sleep in aged mice are impactful enough to affect cognition, quality of life, and/or neurodegenerative pathology could be explored in future studies.

DOI: https://doi.org/10.1101/2025.02.01.636070
Nat Med. 2025 Feb 18.

Engineered heart muscle reinvigorates failing hearts.

Karen O'Leary.



Keywords:  Cardiovascular diseases; Stem cells; Translational research

DOI:  https://doi.org/10.1038/d41591-025-00013-z
NPJ Aging. 2025 Feb 21. 11(1): 12

Characterization of senescence and nuclear reorganization in aging gingival cells.

Christian Fernández, Diego Ormeno, Verónica Villalobos, Mauricio Garrido, Javiera Canelo, Oscar Cerda, Felipe Maldonado, Mónica Caceres.

Cellular senescence is a stress response that limits tumor formation by promoting the removal of damaged cells through the immune system. In this study, we observed accumulation of senescent cells during human aging gingival tissue, by increased levels of γH2A.X, 53BP1, and SAHF, along with a greater distance of H3K9me3 from the nuclear periphery. Additionally, primary gingival fibroblasts from older individuals displayed an enlarged nuclear area and perimeter, accompanied by DNA damage responses and increased Lamin B1 invaginations. The combination of phospho-p38 (Thr180/Tyr182) foci with form factor demonstrated an 79.27% predictive accuracy for aging in gingival fibroblasts, with an AUC of 0.83. In co-culture experiments, our findings revealed that senescent fibroblasts from aged donors exhibit slower and fewer recruitment of PBMCs and decreased levels of the Natural Killer cell receptor ligand MICA/B and the CD112R ligand Nectin-2, suggesting potential impairment in immune surveillance mechanisms during aging.

DOI: https://doi.org/10.1038/s41514-025-00200-9
Front Immunol. 2025 ;16 1534263

Cellular senescence: from homeostasis to pathological implications and therapeutic strategies.

Chunhong Li, Yixiao Yuan, YingDong Jia, Qiang Zhou, Qiang Wang, Xiulin Jiang.

  Cellular aging is a multifactorial and intricately regulated physiological process with profound implications. The interaction between cellular senescence and cancer is complex and multifaceted, senescence can both promote and inhibit tumor progression through various mechanisms. M6A methylation modification regulates the aging process of cells and tissues by modulating senescence-related genes. In this review, we comprehensively discuss the characteristics of cellular senescence, the signaling pathways regulating senescence, the biomarkers of senescence, and the mechanisms of anti-senescence drugs. Notably, this review also delves into the complex interactions between senescence and cancer, emphasizing the dual role of the senescent microenvironment in tumor initiation, progression, and treatment. Finally, we thoroughly explore the function and mechanism of m6A methylation modification in cellular senescence, revealing its critical role in regulating gene expression and maintaining cellular homeostasis. In conclusion, this review provides a comprehensive perspective on the molecular mechanisms and biological significance of cellular senescence and offers new insights for the development of anti-senescence strategies.

Keywords:  aging; cancer; cellular senescence; inflammation; longevity; m6A RNA methylation

DOI:  https://doi.org/10.3389/fimmu.2025.1534263
bioRxiv. 2025 Feb 06. pii: 2025.02.06.636893. [Epub ahead of print]

Regulatory Network Inference of Induced Senescent Midbrain Cell Types Reveals Cell Type-Specific Senescence-Associated Transcriptional Regulators.

Taylor Russo, Jonathan Plessis-Belair, Roger Sher, Markus Riessland.

Cellular senescence of brain cell types has become an increasingly important perspective for both aging and neurodegeneration, specifically in the context of Parkinson's Disease (PD). The characterization of classical hallmarks of senescence is a widely debated topic, whereby the context in which a senescence phenotype is being investigated, such as the cell type, the inducing stressor, and/or the model system, is an extremely important aspect to consider when defining a senescent cell. Here, we describe a cell type-specific profile of senescence through the investigation of various canonical senescence markers in five human midbrain cell lines using chronic 5-Bromodeoxyuridine (BrdU) treatment as a model of DNA damage-induced senescence. We used principal component analysis (PCA) and subsequent regulatory network inference to define both unique and common senescence profiles in the cell types investigated, as well as revealed senescence-associated transcriptional regulators (SATRs). Functional characterization of one of the identified regulators, transcription factor AP4 (TFAP4), further highlights the cell type-specificity of the expression of the various senescence hallmarks. Our data indicates that SATRs modulate cell type-specific profiles of induced senescence in key midbrain cell types that play an important role in the context of aging and PD.

DOI: https://doi.org/10.1101/2025.02.06.636893
Nat Commun. 2025 Feb 20. 16(1): 1794

Activity-based sensing reveals elevated labile copper promotes liver aging via hepatic ALDH1A1 depletion.

Zhenxiang Zhao, Melissa Y Lucero, Shengzhang Su, Eric J Chaney, Jiajie Jessica Xu, Michael Myszka, Jefferson Chan.

Oxidative stress plays a key role in aging and related diseases, including neurodegeneration, cancer, and organ failure. Copper (Cu), a redox-active metal ion, generates reactive oxygen species (ROS), and its dysregulation contributes to aging. Here, we develop activity-based imaging probes for the sensitive detection of Cu(I) and show that labile hepatic Cu activity increases with age, paralleling a decline in ALDH1A1 activity, a protective hepatic enzyme. We also observe an age-related decrease in hepatic glutathione (GSH) activity through noninvasive photoacoustic imaging. Using these probes, we perform longitudinal studies in aged mice treated with ATN-224, a Cu chelator, and demonstrate that this treatment improves Cu homeostasis and preserves ALDH1A1 activity. Our findings uncover a direct link between Cu dysregulation and aging, providing insights into its role and offering a therapeutic strategy to mitigate its effects.

DOI: https://doi.org/10.1038/s41467-025-56585-4
bioRxiv. 2025 Feb 09. pii: 2025.02.08.637273. [Epub ahead of print]

Quiescence modulates age-related changes in the functional capacity of highly proliferative canine lung mesenchymal stromal cell populations.

Nakesha Agyapong, Leslie Dominguez-Ortega, Brian Macdonough, Patrick Mulluso, Sagar Patel, Briti Prajapati, Brian Saville, Andrew Shapiro, Ethan Trim, Kara Battaglia, Jocelyn Herrera, Gianna Garifo-MacPartland, Dianne Newcombe, Latoya Okundaye, Heather Paglia, Julia Paxson.

The functional capacity of highly proliferative cell populations changes with age. Here, we report that the proliferative capacity of canine lung mesenchymal stromal cells (LMSCs) declines with increasing age of the donor. However, other functional changes such as reduced autophagy, reduced migration/wound healing, increased production of reactive oxygen species, and increased senescence are not significantly altered with increasing age. Furthermore, transcriptomic profiling suggests minimal age-related changes. These data suggest that the reduced proliferative capacity of lung LMSCs isolated from aging donors may be associated with reversible cell cycle arrest (quiescence), rather than irreversible cell cycle arrest (senescence). Similar findings have been reported in other systems, including neural and muscle stem cells that are associated with low turnover-rate tissues.

DOI: https://doi.org/10.1101/2025.02.08.637273
Small Methods. 2025 Feb 18. e2402154

Liposome-Enabled Nanomaterials for Muscle Regeneration.

Shuang Wu, Jianqin Lu.

  Muscle regeneration is a vital biological process that is crucial for maintaining muscle function and integrity, particularly for the treatment of muscle diseases such as sarcopenia and muscular dystrophy. Generally, muscular tissues can self-repair and regenerate under various conditions, including acute or chronic injuries, aging, and genetic mutation. However, regeneration becomes challenging beyond a certain threshold, particularly in severe muscle injuries or progressive diseases. In recent years, liposome-based nanotechnologies have shown potential as promising therapeutic strategies for muscle regeneration. Liposomes offer an adaptable platform for targeted drug delivery due to their cell membrane-like structure and excellent biocompatibility. They can enhance drug solubility, stability, and targeted delivery while minimizing systemic side effects by different mechanisms. This review summarizes recent advancements, discusses current applications and mechanisms, and highlights challenges and future directions for possible clinical translation of liposome-based nanomaterials in the treatment of muscle diseases. It is hoped this review offers new insights into the development of liposome-enabled nanomedicine to address current limitations.

Keywords:  liposome; muscle regeneration nanomedicine

DOI:  https://doi.org/10.1002/smtd.202402154
bioRxiv. 2025 Feb 08. pii: 2025.02.06.636954. [Epub ahead of print]

Context-specific interaction of the lipid regulator DIP-2 with phospholipid synthesis in axon regeneration and maintenance.

Seungmee Park, Yishi Jin, Andrew D Chisholm.

Neurons maintain their morphology over prolonged periods of adult life with limited regeneration after injury. C. elegans DIP-2 is a conserved regulator of lipid metabolism that affects axon maintenance and regeneration after injury. Here, we investigated genetic interactions of dip-2 with mutants in genes involved in lipid biosynthesis and identified roles of phospholipids in axon regrowth and maintenance. CEPT-2 and EPT-1 are enzymes catalyzing the final steps in the de novo phospholipid synthesis (Kennedy) pathway. Loss of function mutants of cept-2 or ept-1 show reduced axon regrowth and failure to maintain axon morphology. We demonstrate that CEPT-2 is cell-autonomously required to prevent age-related axonal defects. Interestingly, loss of function in dip-2 led to suppression of the axon regrowth phenotype observed in either cept-2 or ept-2 mutants, suggesting that DIP-2 acts to counterbalance phospholipid synthesis. Our findings reveal the genetic regulation of lipid metabolism to be critical for axon maintenance under injury and during aging.
Article Summary: Little is known about how adult neurons live long with limited regenerative capacity. This study investigates the role of lipid metabolism in sustaining neuronal health in C. elegans. Mutating phospholipid synthetic genes impairs axon regrowth after injury. Lack of DIP-2, a lipid regulator, restores regrowth, suggesting DIP-2 counterbalances phospholipid synthesis. Moreover, neuronal phospholipid synthesis is essential for preventing age-dependent axonal defects. These findings reveal phospholipid biosynthesis is key to axon integrity during aging and injury. As lipid metabolism is implicated in neurological disorders, this study serves as an entry point into investigating neuronal lipid biology under various conditions.

DOI: https://doi.org/10.1101/2025.02.06.636954
Geroscience. 2025 Feb 21.

Persisting blood-brain barrier disruption following cisplatin treatment in a mouse model of chemotherapy-associated cognitive impairment.

Roland Patai, Boglarka Csik, Adam Nyul-Toth, Rafal Gulej, Kiana Vali Kordestan, Siva Sai Chandragiri, Santny Shanmugarama, Stefano Tarantini, Peter Mukli, Anna Ungvari, Andriy Yabluchanskiy, Zoltan Ungvari, Anna Csiszar.

  Chemotherapy-related cognitive impairment, commonly referred to as "chemobrain," significantly affects cancer survivors' quality of life, yet its underlying mechanisms remain unclear. Most chemotherapeutic agents cannot cross the blood-brain barrier (BBB), yet they cause central nervous system side effects, suggesting alternative pathways of toxicity. Given that these drugs interact with the cerebrovascular endothelium at their highest concentrations, it is logical to hypothesize that endothelial damage contributes to these effects. Our recent studies demonstrated that paclitaxel-induced cognitive impairment in a mouse model results in a partial BBB disruption and subsequent neuroinflammation, mediated by chemotherapy-induced endothelial senescence. In this pilot study, we used two-photon microscopy to assess BBB permeability in mice receiving a clinically relevant cisplatin regimen, evaluating the leakage of fluorescent dextran tracers of varying molecular weights. Two months post-treatment, cisplatin-treated mice exhibited significantly increased BBB permeability to smaller molecular tracers (40 kDa, 3 kDa, and 0.3 kDa) compared to controls, indicating sustained BBB disruption. These results align with our findings for paclitaxel and suggest that chemotherapy-induced endothelial damage and senescence play a central role in cognitive impairments. Interventions targeting endothelial health could mitigate these long-term effects, improving cognitive outcomes for cancer survivors.

Keywords:  Aging; Cellular senescence; Cerebral circulation; Chemobrain; Chemotherapy; Cognitive impairment; DNA damage; Endothelial cell; Endothelium; Neuroinflammation; Neurovascular unit; Side effect; Toxicity; VCI

DOI:  https://doi.org/10.1007/s11357-025-01569-x
Food Chem. 2025 Feb 13. pii: S0308-8146(25)00569-2. [Epub ahead of print]476 143318

The mechanism of perilla oil in regulating lipid metabolism.

Jiawei Xia, Yi Wang, Xin Li, Li Liu, Pin Zhang, Wendong Dai, Peng Luo, Guoze Wang, Yanhong Li.

  Emerging science supports the role of lipid metabolism disorders in the occurrence and development of chronic diseases. Dietary intervention has been shown to be an effective strategy for regulating lipid metabolism. Recent studies showed that perilla is rich in various effective ingredients, including fatty acids, flavonoids, and phenolic acids. These ingredients exhibit a myriad of benefits, notably enhancing intestinal health and helping to manage metabolic diseases. Perilla oil stands out as a promising agent for regulating lipid metabolism, underscoring its potential for various health applications. This review introduces the active ingredients in perilla and provides a systematic overview of the mechanism by which perilla oil regulates lipid metabolism to expand its application value. Further research should focus on exploring the dose effect and absorption efficiency of perilla oil in clinical applications.

Keywords:  Intestinal microflora; Lipid metabolism; Perilla oil; Signaling pathways

DOI:  https://doi.org/10.1016/j.foodchem.2025.143318
Front Pharmacol. 2025 ;16 1528604

Targeted ErbB4 receptor activation prevents D-galactose-induced neuronal senescence via inhibiting ferroptosis pathway.

Ji-Ji Dao, Wei Zhang, Chong Liu, Qian Li, Chen-Meng Qiao, Chun Cui, Yan-Qin Shen, Shuang-Xi Chen, Wei-Jiang Zhao.

   Background: Neuronal senescence is a common pathological feature of various neurodegenerative diseases, with ferroptosis playing a significant role. This study aims to investigate the role of ErbB4 receptor activation in preventing D-Galactose (D-gal)-induced neuronal senescence.
Methods: Mice subjected to D-gal-induced aging were administered a small molecule ErbB4 receptor agonist (E4A), identified via virtual screening, melatonin, or a combination of both. Behavioral assessments were conducted to evaluate therapeutic efficacy in memory and cognitive functions. Immunofluorescence staining, western blot, and biochemical assays were primarily employed to assess changes in both senescence- and ferroptosis-related molecules in mouse hippocampal tissues in response to each treatment. Additionally, mouse hippocampal HT22 neuronal cell cultures were utilized to corroborate the in vivo findings.
Results: The targeted activation of ErbB4 receptor by E4A significantly ameliorated the behavioral deficits induced by D-gal in mice, demonstrating an effect comparable to that of melatonin, a natural inhibitor of in vivo senescence and ferroptosis. Both E4A and melatonin mitigated D-gal-induced aging in hippocampal neurons of mice. This was evidenced by the upregulation of Lamin B1 and the downregulation of P53, P21, P16, GFAP, and Iba-1 expression levels. Moreover, D-gal treatment markedly decreased the protein expression of the ferroptosis inhibitor Nrf2 while augmenting the expression of the ferroptosis promoter TFRC. These alterations were partially reversed by the individual administration of E4A and melatonin. In vitro studies further corroborated that D-gal treatment significantly and concurrently induced the expression of senescence markers and ferroptosis promoters. However, both E4A and melatonin were able to significantly reverse these changes. Additionally, E4A markedly ameliorated Erastin-induced ferroptosis in mouse hippocampal neuronal cells.
Conlusion: Our findings suggest that targeted activation of ErbB4 receptor may be a viable strategy for treating neuronal senescence by inhibiting ferroptosis, thereby offering a potential therapeutic avenue for senescence-associated neurodegenerative diseases.

Keywords:  D-galactose; ErbB4 receptor; ferroptosis; hippocampus; neurodegenerative diseases; neuron; senescence; small molecule

DOI:  https://doi.org/10.3389/fphar.2025.1528604
Ann N Y Acad Sci. 2025 Feb 20.

Correction to "Bats as instructive animal models for studying longevity and aging".

DOI: https://doi.org/10.1111/nyas.15312
bioRxiv. 2025 Feb 01. pii: 2025.01.28.635350. [Epub ahead of print]

Multi-tissue transcriptomic aging atlas reveals predictive aging biomarkers in the killifish.

Emma K Costa, Jingxun Chen, Ian H Guldner, Lajoyce Mboning, Natalie Schmahl, Aleksandra Tsenter, Man-Ru Wu, Patricia Moran-Losada, Louis S Bouchard, Sui Wang, Param Priya Singh, Matteo Pellegrini, Anne Brunet, Tony Wyss-Coray.

Aging is associated with progressive tissue dysfunction, leading to frailty and mortality. Characterizing aging features, such as changes in gene expression and dynamics, shared across tissues or specific to each tissue, is crucial for understanding systemic and local factors contributing to the aging process. We performed RNA-sequencing on 13 tissues at 6 different ages in the African turquoise killifish, the shortest-lived vertebrate that can be raised in captivity. This comprehensive, sex-balanced 'atlas' dataset reveals the varying strength of sex-age interactions across killifish tissues and identifies age-altered biological pathways that are evolutionarily conserved. Demonstrating the utility of this resource, we discovered that the killifish head kidney exhibits a myeloid bias during aging, a phenomenon more pronounced in females than in males. In addition, we developed tissue-specific 'transcriptomic clocks' and identified biomarkers predictive of chronological age. We show the importance of sex-specific clocks for selected tissues and use the tissue clocks to evaluate a dietary intervention in the killifish. Our work provides a comprehensive resource for studying aging dynamics across tissues in the killifish, a powerful vertebrate aging model.

DOI: https://doi.org/10.1101/2025.01.28.635350
Mol Biol (Mosk). 2024 Sep-Oct;58(5):58(5): 719-742

[Geroprotective Properties of the ATM Inhibitor KU-60019 in Three Drosophila Species Differing in Lifespan].

L A Koval', N V Zemskaya, N P Pakshina, M V Shaposhnikov, A A Moskalev.

  Serine/threonine protein kinase ATM (ataxia-telangiectasia mutated) performs a number of aging-related functions in the cell. In addition to regulating the cell response to DNA damage, ATM phosphorylates vacuolar ATPase and thus leads to lysosome degradation and cell senescence. The geroprotective potential of the selective ATM inhibitor KU-60019 was studied in three Drosophila species with different lifespans. KU-60019 was shown to increase the lifespan in the long-lived species D. virilis and moderate-lifespan D. melanogaster. However, the lifespan was reduced after KU-60019 treatment in the short-lived species D. kikkawai. KU-60019 was found to increase the survival in hyperthermia, oxidative stress, and starvation in all of the three Drosophila species, but had no effect on age-dependent changes in locomotor activity. Suppression of the tefu gene for an ATM homolog by RNA interference (RNAi) also increased the lifespan and stress tolerance in D. melanogaster compared with control strains. Thus, the effect of KU-60019 on the lifespan was shown to vary among the Drosophila species. The variation might be related to transcriptome differences observed previously and requires further experimental study.

Keywords:  ATM inhibitor; Drosophila; KU-60019; lifespan; spontaneous locomotor activity; stress tolerance

DOI:  https://doi.org/10.31857/S0026898424050042, EDN: HURGGP
bioRxiv. 2025 Feb 05. pii: 2025.01.14.633043. [Epub ahead of print]

Altered relaxation and Mitochondria-Endoplasmic Reticulum Contacts Precede Major (Mal)adaptations in Aging Skeletal Muscle and are Prevented by Exercise.

Ryan J Allen, Ana Kronemberger, Qian Shi, Marshall Pope, Elizabeth Cuadra-Muñoz, Wangkuk Son, Long-Sheng Song, Ethan J Anderson, Renata O Pereira, Vitor A Lira.

Sarcopenia, or age-related muscle dysfunction, contributes to morbidity and mortality. Besides decreases in muscle force, sarcopenia is associated with atrophy and fast-to-slow fiber type switching, which is typically secondary to denervation in humans and rodents. However, very little is known about cellular changes preceding these important (mal)adaptations. To this matter, mitochondria and the sarcoplasmic reticulum are critical for tension generation in myofibers. They physically interact at the boundaries of sarcomeres forming subcellular hubs called mitochondria-endo/sarcoplasmic reticulum contacts (MERCs). Yet, whether changes at MERCs ultrastructure and proteome occur early in aging is unknown. Here, studying young adult and older mice we reveal that aging slows muscle relaxation leading to longer excitation-contraction-relaxation (ECR) cycles before maximal force decreases and fast-to-slow fiber switching takes place. We reveal that muscle MERC ultrastructure and mitochondria-associated ER membrane (MAM) protein composition are also affected early in aging and are closely associated with rate of muscle relaxation. Additionally, we demonstrate that regular exercise preserves muscle relaxation rate and MERC ultrastructure in early aging. Finally, we profile a set of muscle MAM proteins involved in energy metabolism, protein quality control, Ca 2+ homeostasis, cytoskeleton integrity and redox balance that are inversely regulated early in aging and by exercise. These may represent new targets to preserve muscle function in aging individuals.

DOI: https://doi.org/10.1101/2025.01.14.633043