bims-caglex 2025-01-26 papers

bims-caglex

Biomed News

on Cellular aging and life extension

Issue of 2025–01–26
thirty-six papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño

Anti-Aging Tests for Middle Aged Women.
Deep learning and generative artificial intelligence in aging research and healthy longevity medicine.
Downregulated TFPI2 accelerates skin aging by repressing cell cycle via PI3K/Akt/CDC6 pathway.
Nanodevice-Mediated Immune Cell Recruitment: Targeting Senescent Cells via MMP-3-Responsive CXCL12-Coated Nanoparticles.
DNA methylation clocks struggle to distinguish inflammaging from healthy aging, but feature rectification improves coherence and enhances detection of inflammaging.
Comprehensive evaluation of lifespan-extending molecules in C. elegans.
Caloric restriction and its mimetics in heart failure with preserved ejection fraction: mechanisms and therapeutic potential.
RNA molecule rejuvenates ageing mice by restoring old cells.
Involvement of ROS signal in aging and regulation of brain functions.
Reversing Decline in Aging Muscles: Expected Trends, Impacts and Remedies.
AP2A1 modulates cell states between senescence and rejuvenation.
Deciphering the role of cytokines in aging: Biomarker potential and effective targeting.
Aging and injury drive neuronal senescence in the dorsal root ganglia.
Apigenin enhancing oxidative resistance and proteostasis to extend lifespan via PTEN-mediated AKT signalling pathway.
COPD Airway Epithelial Cell-derived Extracellular Vesicles Spread Cellular Senescence via MicroRNA-34a.
Reduced UPF1 levels in senescence impair nonsense-mediated mRNA decay.
Promotion of healthy aging through the nexus of gut microbiota and dietary phytochemicals.
Age-associated microglial transcriptome leads to diminished immunogenicity and dysregulation of MCT4 and P2RY12/P2RY13 related functions.
Ergothioneine improves healthspan of aged animals by enhancing cGPDH activity through CSE-dependent persulfidation.
Cordyceps militaris-Derived Bioactive Gels: Therapeutic and Anti-Aging Applications in Dermatology.
Exosome-based targeted delivery of NF-κB ameliorates age-related neuroinflammation in the aged mouse brain.
The evidence to date: implications of l-ascorbic acid in the pathophysiology of aging.
Production, Isolation, and Characterization of Stable Isotope-Labeled Standards for Mass Spectrometric Measurements of Oxidatively-Damaged Nucleosides in RNA.
Age-Related Decline in Disengaging Spatial Attention in Physiological Aging.
Timing of dietary effects on the epigenome and their potential protective effects against toxins.
OGG1 and MUTYH repair activities promote telomeric 8-oxoguanine induced senescence in human fibroblasts.
Irisin reshapes bone metabolic homeostasis to delay age-related osteoporosis by regulating the multipotent differentiation of BMSCs via Wnt pathway.
∆9-Tetrahydrocannabinol Increases Growth Factor Release by Cultured Adipose Stem Cells and Adipose Tissue in vivo.
Unfolded protein responses: Dynamic machinery in wound healing.
LncRNA 3222401L13Rik Is Upregulated in Aging Astrocytes and Regulates Neuronal Support Function Through Interaction with Npas3.
Intestine-specific disruption of mitochondrial superoxide dismutase extends longevity.
The interplay of senescence and MMPs in myocardial infarction: implications for cardiac aging and therapeutics.
Biomolecular Condensates in Telomere Maintenance of ALT Cancer Cells.
Spontaneous blinking and brain health in aging: Large-scale evaluation of blink-related oscillations across the lifespan.
PLK3 weakens antioxidant defense and inhibits proliferation of porcine Leydig cells under oxidative stress.
Cellular senescence in the tumor with a bone niche microenvironment: friend or foe?

J Menopausal Med. 2024 Dec;30(3): 164-169

Anti-Aging Tests for Middle Aged Women.

Min-Sun Kim, Tae-Hee Kim.

  The interest in aging and anti-aging research has increased significantly in recent years, leading to rapid expansion in the anti-aging market. Aging is associated with gradual physiological changes and an elevated risk of age-related ailments, and is divided into three categories: usual aging, successful aging, and pathological aging. Each category is associated with distinct implications for health and well-being. Middle-aged women who experience accelerated physiological changes that are intensified by hormonal changes during menopause are particularly vulnerable to chronic diseases. The importance of anti-aging tests is increasing since they enable early identification and intervention. Telomere length, oxidative stress markers, DNA repair markers, RNA profiles, inflammatory markers, hormone levels, and epigenetic changes are some molecular parameters studied to test for aging. In addition, a thorough review of middle-aged women's anti-aging profiles also includes monitoring the vitamin D levels and assessing the effects of endocrine-disrupting substances on ovarian aging. The application of personalized medicine paradigms, utilizing various diagnostic methods, will enable accurate risk prediction and the implementation of focused therapies, ultimately promoting the extension of health span and the improvement of quality of life in middle-aged women.

Keywords:  Aging; Middle aged; Telomere

DOI:  https://doi.org/10.6118/jmm.24012
Aging (Albany NY). 2025 Jan 16. 17

Deep learning and generative artificial intelligence in aging research and healthy longevity medicine.

Dominika Wilczok.

  With the global population aging at an unprecedented rate, there is a need to extend healthy productive life span. This review examines how Deep Learning (DL) and Generative Artificial Intelligence (GenAI) are used in biomarker discovery, deep aging clock development, geroprotector identification and generation of dual-purpose therapeutics targeting aging and disease. The paper explores the emergence of multimodal, multitasking research systems highlighting promising future directions for GenAI in human and animal aging research, as well as clinical application in healthy longevity medicine.

Keywords:  aging; deep aging clocks; deep learning; generative artificial intelligence; healthy longevity medicine

DOI:  https://doi.org/10.18632/aging.206190
J Invest Dermatol. 2025 Jan 21. pii: S0022-202X(25)00033-8. [Epub ahead of print]

Downregulated TFPI2 accelerates skin aging by repressing cell cycle via PI3K/Akt/CDC6 pathway.

Fan Wang, Caitan Yi, Yun Zhong, Lei Zhou, Xin Meng, Rui Mao, Yi Guo, Hongfu Xie, Yiya Zhang, Yingxue Huang, Ji Li.

  Tissue factor pathway inhibitor 2 (TFPI2) is known to regulate the proliferation of various cell types and tumor tissues; however, its role in the process of skin aging has not been elucidated. In this study, we identify TFPI2 as a potential antagonist of aging. Our findings indicate that TFPI2 expression is downregulated in aging skin tissues and senescent human dermal fibroblasts (HDFs), and that the depletion of TFPI2 accelerates the senescence of HDFs and the aging of skin. Mechanistically, RNA-seq analysis identifies that cell division cycle 6 (CDC6), a protein associated with the cell cycle, acts as a downstream target of TFPI2. Further liquid chromatography-mass spectrometry (LC-MS) analysis confirmed that TFPI2 interacts with p85β to activate the PI3K/Akt pathway. Subsequent experiments revealed that the activation of the PI3K/Akt pathway alleviates mitigates senescence in HDFs by promoting CDC6 expression and facilitating cell cycle progression. Collectively, these findings underscore the crucial role of the TFPI2/PI3K/Akt/CDC6 pathway in the process of skin aging, highlighting its potential in the development of anti-aging interventions.

Keywords:  CDC6; Celluar Senescence; PI3K/Akt; Skin aging; TFPI2

DOI:  https://doi.org/10.1016/j.jid.2024.11.028
ACS Appl Mater Interfaces. 2025 Jan 21.

Nanodevice-Mediated Immune Cell Recruitment: Targeting Senescent Cells via MMP-3-Responsive CXCL12-Coated Nanoparticles.

Blanca Escriche-Navarro, Eva Garrido, Sandra Clara-Trujillo, Anna Labernadie, Félix Sancenon, Alba García-Fernández, Ramón Martínez-Máñez.

  Senescent cells are involved in age-related disorders in different organs and are therapeutic targets for fibrotic and chronic pathologies. Immune-modulating agents, able to enhance senescent cell detection and elimination by endogenous immune cells, have emerged as pharmacological strategies. We report herein a nanoparticle for immune cell-mediated senolytic therapy designed to recruit immune cells in response to specific enzymatic matrix metalloproteinase-3 (MMP-3) activity in the senescence-associated secretory phenotype. For this, mesoporous silica nanoparticles (MSNs) are coated with a peptide substrate of the metalloproteinase MMP-3, and the peptide is decorated with chemokine CXCL12 that enhances immune cell recruitment (NPs@CXCL12). Controlled release studies confirmed the progressive and specific release of CXCL12 in the presence of MMP-3. The ability of immune cell recruitment in response to a senescent microenvironment (senescent WI-38 fibroblasts) is confirmed by Transwell migration assays with green fluorescent Jurkat T-cells, showing NPs@CXCL12 has an enhanced chemotaxis effect toward senescent cells compared to free CXCL12 (2-fold). Moreover, the cytotoxic capacity of human primary natural killer (NK) cells over senescent WI-38 is also confirmed, and their migration trajectories in response to NPs@CXCL12 or free CXCL12 are monitored by using a microfluidic device. Results confirm the ability of NPs@CXCL12 to generate a chemotactic gradient able to attract NK cells. When compared with free CXCL12, the NPs@CXCL12 system showed a reduction of up to 15.56% in the population of NK cells migrating toward free CXCL12 under competitive conditions. This study demonstrates the potential of designing nanoparticles to recruit immune cells under specific responses to eliminate senescent cells. Results confirm that NPs@CXCL12 can effectively establish a chemotactic gradient to attract NK cells.

Keywords:  CXCL12; matrix metalloproteinase-3; mesoporous silica nanoparticles; senescence, immune cells

DOI:  https://doi.org/10.1021/acsami.4c17748
Geroscience. 2025 Jan 18.

DNA methylation clocks struggle to distinguish inflammaging from healthy aging, but feature rectification improves coherence and enhances detection of inflammaging.

Colin M Skinner, Michael J Conboy, Irina M Conboy.

  Biological age estimation from DNA methylation and determination of relevant biomarkers is an active research problem which has predominantly been tackled with black-box penalized regression. Machine learning is used to select a small subset of features from hundreds of thousands of CpG probes and to increase generalizability typically lacking with ordinary least-squares regression. Here, we show that such feature selection lacks biological interpretability and relevance in the clocks of the first and next generations and clarify the logic by which these clocks systematically exclude biomarkers of aging and age-related disease. Moreover, in contrast to the assumption that regularized linear regression is needed to prevent overfitting, we demonstrate that hypothesis-driven selection of biologically relevant features in conjunction with ordinary least squares regression yields accurate, well-calibrated, generalizable clocks with high interpretability. We further demonstrate that the interplay of inflammaging-related shifts of predictor values and their corresponding weights, which we term feature shifts, contributes to the lack of resolution between health and inflammaging in conventional linear models. Lastly, we introduce a method of feature rectification, which aligns these shifts to improve the distinction of age predictions for healthy people vs. patients with various chronic inflammation diseases.

Keywords:  Aging; DNA methylation; DNA methylation clock; Elastic net regression; Feature selection; Forward stepwise selection; L1 penalty; PBMc clock

DOI:  https://doi.org/10.1007/s11357-024-01460-1
Aging Cell. 2025 Jan 24. e14424

Comprehensive evaluation of lifespan-extending molecules in C. elegans.

Grace B Phelps, Jonas Morin, Carla Pinto, Lucas Schoenfeldt, Sebastien Guilmot, Alejandro Ocampo, Kevin Perez.

  The nematode C. elegans has long served as a gold-standard model organism in aging research, particularly since the discovery of long-lived mutants in conserved aging pathways including daf-2 (IGF1) and age-1 (PI3K). Its short lifespan and small size make it highly suitable for high-throughput experiments. While numerous molecules have been tested for their effects on C. elegans lifespan, consensus is still lacking regarding the most effective and reproducible compounds. Confounding effects, especially those related to drug-bacteria interactions, remain a contentious issue in the literature. In this study, we evaluated 16 of the most frequently reported lifespan-extending molecules in C. elegans, examining their effects on lifespan with two different diets (live and UV-killed OP50). In addition, we assessed the compounds' impact on bacterial growth, their effects on various nematode strains, and the impact of the starting age of treatment. Our findings first confirmed robust lifespan extension by many, but not all, of the 16 tested compounds from the literature, and revealed that some of them could be combined to obtain additive effects. Additionally, we showed that some of these compounds also extend lifespan in the fly D. melanogaster, demonstrating a conserved effect across species. Finally, by expanding our screen to a broader pool of molecules, we identified novel lifespan-extending compounds in C. elegans.

Keywords:   C. elegans ; aging; diet; drugs; lifespan; screening; worms

DOI:  https://doi.org/10.1111/acel.14424
Cardiovasc Diabetol. 2025 Jan 18. 24(1): 21

Caloric restriction and its mimetics in heart failure with preserved ejection fraction: mechanisms and therapeutic potential.

Alexander Fuerlinger, Alina Stockner, Simon Sedej, Mahmoud Abdellatif.

  The global increase in human life expectancy, coupled with an unprecedented rise in the prevalence of obesity, has led to a growing clinical and socioeconomic burden of heart failure with preserved ejection fraction (HFpEF). Mechanistically, the molecular and cellular hallmarks of aging are omnipresent in HFpEF and are further exacerbated by obesity and associated metabolic diseases. Conversely, weight loss strategies, particularly caloric restriction, have shown promise in improving health status in patients with HFpEF and are considered the gold standard for promoting longevity and healthspan (disease-free lifetime) in model organisms. In this review, we implicate fundamental mechanisms of aging in driving HFpEF and elucidate how caloric restriction mitigates the disease progression. Furthermore, we discuss the potential for pharmacologically mimicking the beneficial effects of caloric restriction in HFpEF using clinically approved and emerging caloric restriction mimetics. We surmise that these compounds could offer novel therapeutic avenues for HFpEF and alleviate the challenges associated with the implementation of caloric restriction and other lifestyle modifications to reduce the burden of HFpEF at a population level.

Keywords:  Aging; Caloric restriction mimetics; Fasting; GLP-1A; HFpEF; Obesity; SGLT2

DOI:  https://doi.org/10.1186/s12933-024-02566-8
Nature. 2025 Jan 17.

RNA molecule rejuvenates ageing mice by restoring old cells.

Chris Simms.



Keywords:  Ageing

DOI:  https://doi.org/10.1038/d41586-025-00032-3
J Physiol Sci. 2024 Dec 21. pii: S1880-6546(24)00984-3. [Epub ahead of print]75(1): 100003

Involvement of ROS signal in aging and regulation of brain functions.

Sho Kakizawa.

  Reactive oxygen species (ROS) are redox-signaling molecules involved in aging and lifestyle-related diseases. In the brain, in addition to the production of ROS as byproducts of metabolism, expression of ROS synthases has recently been demonstrated, suggesting possible involvement of ROS in various brain functions. This review highlights current knowledge on the relationship between ROS and brain functions, including their contribution to age-related decline in synaptic plasticity and cognitive function. While most studies demonstrate either the positive or negative effects of ROS on synaptic plasticity, the dual effects of ROS at individual synapses have been demonstrated recently in the mouse cerebellum. Furthermore, the cooperative interaction between these two effects determines the direction of synaptic plasticity. It is anticipated that further elucidation of both the positive and negative effects of ROS on brain function will lead to the development of more effective therapeutic strategies with fewer side effects for ROS-related brain dysfunction.

Keywords:  Aging; Cerebellum; Long-term depression; Long-term potentiation; Reactive oxygen species; Synaptic plasticity

DOI:  https://doi.org/10.1016/j.jphyss.2024.100003
J Funct Morphol Kinesiol. 2025 Jan 11. pii: 29. [Epub ahead of print]10(1):

Reversing Decline in Aging Muscles: Expected Trends, Impacts and Remedies.

Matthew Halma, Paul Marik, Joseph Varon, Jack Tuszynski.

  Background: Age-related decline in musculoskeletal function is a significant concern, particularly in Western countries facing demographic shifts and increased healthcare demands. This review examines the typical trajectories of musculoskeletal deterioration with age and evaluates the effectiveness of various interventions in preventing or reversing these changes. Methods: The review analyzes documented rates of decline across multiple parameters, including muscle mass, Type II muscle fiber reduction, and decreased motor unit firing rates. It examines evidence from studies on targeted interventions aimed at reversing these trends or preventing further decline. Results: The evidence suggests that multimodal interventions, including strength training can effectively maintain or improve physical function in aging adults. These interventions have shown potential in altering the trajectory of age-related decline in musculoskeletal function. Conclusions. The findings of this review have important implications for healthcare providers and policymakers in addressing the challenges of an aging population. By providing a framework for understanding and addressing age-related physical decline through evidence-based interventions, this review offers potential strategies for reducing healthcare costs and improving the quality of life for older adults.

Keywords:  cardiovascular fitness; cognitive function; healthy aging; longevity interventions; metabolic health; musculoskeletal strength; physical performance tests; quality of life in older people

DOI:  https://doi.org/10.3390/jfmk10010029
Cell Signal. 2025 Jan 21. pii: S0898-6568(25)00029-4. [Epub ahead of print] 111616

AP2A1 modulates cell states between senescence and rejuvenation.

Pirawan Chantachotikul, Shiyou Liu, Kana Furukawa, Shinji Deguchi.

  Aging proceeds with the accumulation of senescent cells in multiple organs. These cells exhibit increased size compared to young cells, which promotes further senescence and age-related diseases. Currently, the molecular mechanism behind the maintenance of such huge cell architecture undergoing senescence remains poorly understood. Here we focus on the reorganization of actin stress fibers induced upon replicative senescence in human fibroblasts, widely used as a senescent cell model. We identified, together with our previous proteomic study, that AP2A1 (alpha 1 adaptin subunit of the adaptor protein 2) is upregulated in senescent cells along the length of enlarged stress fibers. Knockdown of AP2A1 reversed senescence-associated phenotypes, exhibiting features of cellular rejuvenation, while its overexpression in young cells advanced senescence phenotypes. Similar functions of AP2A1 were identified in UV- or drug-induced senescence and were observed in epithelial cells as well. Furthermore, we found that AP2A1 is colocalized with integrin β1, and both proteins move linearly along stress fibers. With the observations that focal adhesions are enlarged in senescent cells and that this coincides with strengthened cell adhesion to the substrate, these results suggest that senescent cells maintain their large size by reinforcing their effective anchorage through integrin β1 translocation along stress fibers. This mechanism may work efficiently in senescent cells, compared with a case relying on random diffusion of integrin β1, given the enlarged cell size and resulting increase in travel time and distance for endocytosed vesicle transportation.

Keywords:  AP2A1; Cell size control; Focal adhesions; Rejuvenation; Senescence; Stress fibers

DOI:  https://doi.org/10.1016/j.cellsig.2025.111616
Mech Ageing Dev. 2025 Jan 18. pii: S0047-6374(25)00012-0. [Epub ahead of print]224 112036

Deciphering the role of cytokines in aging: Biomarker potential and effective targeting.

Panagiotis Poulios, Stamoulis Skampouras, Christina Piperi.

  Aging is often characterized by chronic inflammation, immune system dysregulation, and cellular senescence with chronically elevated levels of pro-inflammatory cytokines. These small glycoproteins are mainly secreted by immune cells, mediating intercellular communication and immune system modulation through inflammatory signaling. Their pro- and anti-inflammatory effects make them a noteworthy research topic as well as a promising ally in combating inflammation and the aging process. Cytokines exert a synergistic role in aging and disease and may prove useful biomarkers of tissue-specific dysregulation, disease diagnosis and monitoring, presenting potential therapeutic options as anti-inflammatory and senolytic medications. In this review, we address the cellular and molecular mechanisms implicating cytokines in the aging process and related diseases, highlighting their biomarker potential. We focus on the current therapeutic strategies, including specific pharmaceutical agents, supplements, a balanced diet, and healthy habits such as exercise, stress management, and caloric restriction.

Keywords:  Aging; Cytokines; Inflammation; Lifestyle factors; Senolytics

DOI:  https://doi.org/10.1016/j.mad.2025.112036
bioRxiv. 2024 Jan 22. pii: 2024.01.20.576299. [Epub ahead of print]

Aging and injury drive neuronal senescence in the dorsal root ganglia.

Lauren J Donovan, Chelsie L Brewer, Sabrina F Bond, Aleishai Pena Lopez, Linus H Hansen, Claire E Jordan, Oscar C González, Luis de Lecea, Julie A Kauer, Vivianne L Tawfik.

Aging negatively impacts central nervous system function; however, the cellular impact of aging in the peripheral nervous system remains poorly understood. Aged individuals are more likely to experience increased pain and slower recovery after trauma. Such injury can damage vulnerable peripheral axons of dorsal root ganglion (DRG) neurons resulting in somatosensory dysfunction. One cellular mechanism common to both aging and injury is cellular senescence, a complex cell state that can contribute to the aged pro-inflammatory environment. We uncovered, for the first time, DRG neuron senescence in the context of aging and pain-inducing peripheral nerve injury in young and aged mice. Aged DRG neurons displayed multiple markers of senescence (SA-β-gal, p21, p16, IL6) when compared to young DRG neurons. Peripheral nerve injury triggered a further accumulation of senescent DRG neurons over time post-injury in young and aged DRG. These senescent neurons were dynamic and heterogeneous in their expression of senescence markers, p16, p21, and senescence-associated secretory phenotype (SASP) expression of IL6, which was influenced by age. An electrophysiological characterization of senescence marker-expressing neurons revealed high-firing and nociceptor-like phenotypes within these populations. In addition, we observed improvement in nociceptive behaviors in young and aged nerve-injured mice after treatment with a senolytic agent that eliminates senescent cells. Finally, we confirmed in human post-mortem DRG samples that neuronal senescence is present and increases with age. Overall, we describe a susceptibility of the peripheral nervous system to neuronal senescence with age or injury that may be a targetable mechanism to treat sensory dysfunction, such as chronic pain, particularly in aged populations.

DOI: https://doi.org/10.1101/2024.01.20.576299
Biochim Biophys Acta Mol Basis Dis. 2025 Jan 16. pii: S0925-4439(25)00015-8. [Epub ahead of print] 167670

Apigenin enhancing oxidative resistance and proteostasis to extend lifespan via PTEN-mediated AKT signalling pathway.

Zhengqiong Sun, Lei Li, Lei Zhang.

  Aging is a complicated process, featuring the progressive deterioration of physiological functions and a heightened susceptibility to diseases including neurodegenerative disorders, cardiovascular diseases, and cancer. Apigenin, a flavonoid existing in various plants, has attracted attention due to its potential role in anti-aging. In this investigation, the potential effect of apigenin on extending lifespan in Saccharomyces cerevisiae (yeast) and Drosophila melanogaster (flies) was explored. The results indicate that apigenin significantly extends both replicative and chronological life duration in yeast, as well as longevity in male and female flies. Apigenin treatment also improves resistance to oxidative stress in both organisms, as manifested by enhanced survival, decreased reactive oxygen species (ROS) levels and upregulation of antioxidant enzymes. Furthermore, apigenin activates crucial elements of the proteostasis network (PN), such as upregulation of proteostasis-related enzymes activity and genes expression. Network analysis revealed that apigenin affects aging conserved in the longevity-regulating pathway. Notably, Pten is a hub target in flies. Apigenin regulated DmPten at both mRNA and protein expression level while modulating downstream targets, including the phosphorylation of AKT and associated signalling pathways. In a high-sucrose diet (HSD) model, Apigenin treatment extended lifespan, reduced hemolymph glucose levels, enhanced Pten expression, suppressed AKT phosphorylation, and modulated the phosphorylation status of S6K and expression of DmFoxo. These results demonstrate that apigenin could serve as a longevity research object and potential therapeutic drug for promoting health and longevity through its antioxidant and proteostatic properties.

Keywords:  Aging; Antioxidant; Apigenin; Diabetes; Network pharmacology; PTEN; Proteostasis

DOI:  https://doi.org/10.1016/j.bbadis.2025.167670
Am J Respir Cell Mol Biol. 2025 Jan 21.

COPD Airway Epithelial Cell-derived Extracellular Vesicles Spread Cellular Senescence via MicroRNA-34a.

Justine V Devulder, Jonathan R Baker, Peter S Fenwick, Lina Odqvist, Louise E Donnelly, Peter J Barnes.

  Chronic obstructive pulmonary disease (COPD) is associated with the acceleration of lung aging, and the accumulation of senescent cells in lung tissue. MicroRNA (miR)-34a induces senescence by suppressing the anti-aging molecule, sirtuin-1 (SIRT1). Senescent cells spread senescence to neighbouring and distant cells, favouring COPD progression and its comorbidities. Mechanisms for spreading senescence remain undetermined but may be mediated by the transfer of microRNAs in extracellular vesicles. We analysed the miRNA content of extracellular vesicles in COPD and explored their effect on cellular senescence of healthy cells. EVs were isolated from small airway epithelial cells (SAEC) from healthy donors or COPD patients. Recipient healthy SAEC were cultured with EVs and the expression of miR-34a and markers of cellular senescence, p21CIP1 and SIRT1, were measured. We have shown that EVs from COPD cells induce senescence in healthy recipient cells via the selective transfer of miR-34a. COPD SAEC produce increased numbers of EVs enriched with miR-34a. EVs are taken up by healthy cells, resulting in reduced expression of the anti-aging molecule sirtuin-1 and increased expression of markers of senescence, like p21CIP1 and positive staining for senescence-associated β-galactosidase, which were blocked by a specific miR-34a antagomir. Our findings provide evidence of the mechanism by which EVs spread cellular senescence in human primary cells via miR-34a, rather than via soluble mediators. EVs enriched with miR-34a may spread senescence locally, accounting for disease progression, but also provide a mechanism for distant spread to account for comorbidities and multimorbidity of the elderly.

Keywords:  COPD; Cellular senescence; Extracellular vesicles; microRNAs

DOI:  https://doi.org/10.1165/rcmb.2024-0183OC
Commun Biol. 2025 Jan 18. 8(1): 83

Reduced UPF1 levels in senescence impair nonsense-mediated mRNA decay.

Dahyeon Koh, Yebin Lee, Kyuchan Kim, Hyeong Bin Jeon, Chaehwan Oh, Sangik Hwang, Minjung Lim, Kwang-Pyo Lee, Yeonkyoung Park, Yong Ryoul Yang, Yoon Ki Kim, Donghwan Shim, Myriam Gorospe, Ji Heon Noh, Kyoung Mi Kim.

Cells regulate gene expression through various RNA regulatory mechanisms, and this regulation often becomes less efficient with age, contributing to accelerated aging and various age-related diseases. Nonsense-mediated mRNA decay (NMD), a well-characterized RNA surveillance mechanism, degrades aberrant mRNAs with premature termination codons (PTCs) to prevent the synthesis of truncated proteins. While the role of NMD in cancer and developmental and genetic diseases is well documented, its implications in human aging remain largely unexplored. This study reveals a significant decline in the levels of the protein UPF1, a key player in NMD, during cellular senescence. Additionally, NMD substrates accumulate in senescent cells, along with decreased levels of cap-binding protein 80/20 (CBP80/20)-dependent translation (CT) factors and reduced binding to active polysomes, indicating reduced efficiency of NMD. Moreover, knockdown of UPF1 in proliferating WI-38 cells induces senescence, as evidenced by increased senescence-associated β-galactosidase activity, alterations in senescence-associated molecular markers, increased endogenous γ-H2AX levels, and reduced cell proliferation. These findings suggest that the decline in UPF1 levels during cellular senescence accelerates the senescent phenotype by impairing NMD activity and the consequent accumulation of abnormal mRNA.

DOI: https://doi.org/10.1038/s42003-025-07502-4
Adv Nutr. 2025 Jan 18. pii: S2161-8313(25)00012-2. [Epub ahead of print] 100376

Promotion of healthy aging through the nexus of gut microbiota and dietary phytochemicals.

Laura M Beaver, Paige E Jamieson, Carmen P Wong, Mahak Hosseinikia, Jan F Stevens, Emily Ho.

  Aging is associated with the decline of tissue and cellular functions, which can promote the development of age-related diseases like cancer, cardiovascular disease, neurodegeneration, and disorders of the musculoskeletal and immune systems. Healthspan is the length of time an individual is in good health and free from chronic diseases and disabilities associated with aging. Two modifiable factors that can influence healthspan, promote healthy aging, and prevent the development of age-related diseases, are the diet and microbiota in the gastrointestinal tract (gut microbiota). This review will discuss how dietary phytochemicals and gut microbiota can work in concert to promote a healthy gut and healthy aging. First an overview is provided of how the gut microbiota influences healthy aging through its impact on gut barrier integrity, immune function, mitochondria function and oxidative stress. Next, the mechanisms by which phytochemicals effect gut health, inflammation, and nurture a diverse and healthy microbial composition are discussed. Lastly, the gut microbiota can directly influence health by producing bioactive metabolites from phytochemicals in food like urolithin A, equol, hesperetin and sulforaphane. These and other phytochemical derived microbial metabolites that may promote healthspan are discussed. Importantly, an individual's capacity to produce health promoting microbial metabolites from cruciferous vegetables, berries, nuts, citrus and soy products will be dependent on the specific bacteria present in the individual's gut.

Keywords:  diet; dysbiosis; gut health; gut microbiome; healthspan; lifespan; microbial metabolite; phytochemicals

DOI:  https://doi.org/10.1016/j.advnut.2025.100376
Cell Death Discov. 2025 Jan 19. 11(1): 16

Age-associated microglial transcriptome leads to diminished immunogenicity and dysregulation of MCT4 and P2RY12/P2RY13 related functions.

Martin Škandík, Lara Friess, Guillermo Vázquez-Cabrera, Lily Keane, Kathleen Grabert, Mireia Cruz De Los Santos, Mercedes Posada-Pérez, Austeja Baleviciute, Mathilde Cheray, Bertrand Joseph.

The aging process is marked by a time-dependent deterioration in cellular functions, particularly the immune and neural systems. Understanding the phenotype acquisition of microglia, the sentinel immune cells of the brain, is crucial for understanding the nature of age-related neurological diseases. However, the specific phenotype adopted by microglia during aging remains a subject of debate and is contingent on the chosen experimental model. To address these unresolved questions, we employed a novel and highly controlled approach utilizing long-term cultivated BV-2 microglia, exempted from additional external stimuli. Our findings revealed that aged microglial cells, in comparison to their younger counterparts, acquire a distinct gene expression profile, primarily characterized by alterations in microglial immune response. Indeed, pro-inflammatory stimulated aged and young BV-2 microglia exhibited similar transcriptomic profiles, yet the response intensity to the stimulus was markedly muted in the aged microglia. Functional neurotoxic assays confirmed diminished neuronal death in coculture with aged, activated microglia, underscoring a compromised immune response. Furthermore, a subsequent comparative analysis of aged BV-2 microglia with established transcriptomic microglial datasets from aged mice and humans identified 13 overlapping genes, laying the foundation for identifying core microglial aging signature. Particularly noteworthy were SLC16A3 and P2RY13, which consistently exhibited upregulation and downregulation, respectively, across all datasets. Additionally, four other genes-CAPG, LGALS3BP, NRIP1, and P2RY12-were found to share regulatory patterns in response to both aging and extrinsic activation. An in-depth investigation focused on SLC16A3, encoding the high-affinity lactate transporter MCT4, revealed disruptions in extracellular acidification rate and lactate concentration with age. Microglial purine sensing and motility capacities, regulated by P2RY12/P2RY13, displayed age-related alterations. Remarkably, protein analysis in human brain tissue validated the observed upregulation of MCT4 and downregulation of P2RY12 in aged microglia. In conclusion, our study unveils a distinct phenotype in aged microglia characterized by compromised immune responsiveness. Through the integration of in vitro cultured BV-2 microglia with primary microglia datasets, we identify critical molecular determinants of microglial cellular aging confirmed in human-aged brain tissue. This comprehensive approach offers potential insights for understanding and potentially reprogramming aged microglia, with implications for combating age-related neurological disorders.

DOI: https://doi.org/10.1038/s41420-025-02295-1
Cell Metab. 2025 Jan 15. pii: S1550-4131(24)00490-X. [Epub ahead of print]

Ergothioneine improves healthspan of aged animals by enhancing cGPDH activity through CSE-dependent persulfidation.

Dunja Petrovic, Luke Slade, Yiorgos Paikopoulos, Davide D'Andrea, Nevena Savic, Ana Stancic, Jan Lj Miljkovic, Thibaut Vignane, Maria Kyriaki Drekolia, Dusan Mladenovic, Nikola Sutulovic, Alice Refeyton, Milica Kolakovic, Vladimir M Jovanovic, Jasmina Zivanovic, Marko Miler, Valentina Vellecco, Vincenzo Brancaleone, Mariarosaria Bucci, Alva M Casey, ChakShun Yu, Siva Swapna Kasarla, Karl William Smith, Ayten Kalfe-Yildiz, Martin Stenzel, Antonio Miranda-Vizuete, Roland Hergenröder, Prasad Phapale, Olivera Stanojlovic, Ivana Ivanovic-Burmazovic, Marija Vlaski-Lafarge, Sofia-Iris Bibli, Michael P Murphy, Vesna Otasevic, Milos R Filipovic.

  Ergothioneine (ET), a dietary thione/thiol, is receiving growing attention for its possible benefits in healthy aging and metabolic resilience. Our study investigates ET's effects on healthspan in aged animals, revealing lifespan extension and enhanced mobility in Caenorhabditis elegans, accompanied by improved stress resistance and reduced age-associated biomarkers. In aged rats, ET administration enhances exercise endurance, muscle mass, and vascularization, concomitant with higher NAD+ levels in muscle. Mechanistically, ET acts as an alternative substrate for cystathionine gamma-lyase (CSE), stimulating H2S production, which increases protein persulfidation of more than 300 protein targets. Among these, protein-persulfidation-driven activation of cytosolic glycerol-3-phosphate dehydrogenase (cGPDH) primarily contributes to the ET-induced NAD+ increase. ET's effects are abolished in models lacking CSE or cGPDH, highlighting the essential role of H2S signaling and protein persulfidation. These findings elucidate ET's multifaceted actions and provide insights into its therapeutic potential for combating age-related muscle decline and metabolic perturbations.

Keywords:  NAD; ergothioneine; healthspan; hydrogen sulfide; persulfidation

DOI:  https://doi.org/10.1016/j.cmet.2024.12.008
Gels. 2025 Jan 03. pii: 33. [Epub ahead of print]11(1):

Cordyceps militaris-Derived Bioactive Gels: Therapeutic and Anti-Aging Applications in Dermatology.

Trung Quang Nguyen, Thinh Van Pham, Yusuf Andriana, Minh Ngoc Truong.

  Cordyceps militaris is a medicinal mushroom widely utilized in traditional East Asian medicine, recognized for its diverse therapeutic properties. This review explores the potential of C. militaris-derived bioactive gels for applications in dermatology and skincare, with a particular focus on their therapeutic and anti-aging benefits. In response to the rising incidence of skin cancers and the growing demand for natural bioactive ingredients, C. militaris has emerged as a valuable source of functional compounds, including cordycepin, polysaccharides, and adenosine. These compounds exhibit multiple bioactivities, including apoptosis induction, cell cycle arrest, and anti-inflammatory effects, which have been shown to be particularly effective against melanoma and other skin cancers. Additionally, the antioxidant properties of C. militaris enhance skin resilience by scavenging reactive oxygen species, reducing oxidative stress, and promoting collagen synthesis, thereby addressing skin health and anti-aging requirements. The potential for incorporating C. militaris compounds into gel-based formulations for skincare is also examined, either as standalone bioactives or in combination with synergistic ingredients. Emphasis is placed on the necessity of clinical trials and standardization to establish the safety, efficacy, and reproducibility of such applications. By providing a safer alternative to synthetic agents, C. militaris-derived bioactive gels represent a promising advancement in dermatology and skincare.

Keywords:  Cordyceps militaris; anti-aging; bioactive compounds; dermatology; skincare; therapeutic properties

DOI:  https://doi.org/10.3390/gels11010033
Exp Mol Med. 2025 Jan 20.

Exosome-based targeted delivery of NF-κB ameliorates age-related neuroinflammation in the aged mouse brain.

Chae-Jeong Lee, Seung Hyun Jang, Jiwoo Lim, Hyunju Park, So-Hee Ahn, Seon Young Park, Hyangmi Seo, Soo-Jin Song, Jung-A Shin, Chulhee Choi, Heon Yung Gee, Youn-Hee Choi.

Neuroinflammation, a significant contributor to various neurodegenerative diseases, is strongly associated with the aging process; however, to date, no efficacious treatments for neuroinflammation have been developed. In aged mouse brains, the number of infiltrating immune cells increases, and the key transcription factor associated with increased chemokine levels is nuclear factor kappa B (NF-κB). Exosomes are potent therapeutics or drug delivery vehicles for various materials, including proteins and regulatory genes, to target cells. In the present study, we evaluated the therapeutic efficacy of exosomes loaded with a nondegradable form of IκB (Exo-srIκB), which inhibits the nuclear translocation of NF-κB to suppress age-related neuroinflammation. Single-cell RNA sequencing revealed that these anti-inflammatory exosomes targeted macrophages and microglia, reducing the expression of inflammation-related genes. Treatment with Exo-srIκB also suppressed the interactions between macrophages/microglia and T and B cells in the aged brain. We demonstrated that Exo-srIκB successfully alleviates neuroinflammation by primarily targeting activated macrophages and partially modulating the functions of age-related interferon-responsive microglia in the brain. Thus, our findings highlight Exo-srIκB as a potential therapeutic agent for treating age-related neuroinflammation.

DOI: https://doi.org/10.1038/s12276-024-01388-8
J Physiol Sci. 2024 ;pii: S1880-6546(24)00114-8. [Epub ahead of print]74(1): 29

The evidence to date: implications of l-ascorbic acid in the pathophysiology of aging.

Ayami Sato, Yoshitaka Kondo, Akihito Ishigami.

  L-Ascorbic acid, commonly known as vitamin C, has been used not only for disease prevention and in complementary and alternative medicine, but also for anti-aging purposes. However, the scientific evidence is not yet sufficient. Here, we review the physiological functions of vitamin C and its relationship with various pathological conditions, including our previous findings, and discuss the prospects of its application in healthy longevity. In summary, vitamin C levels are associated with lifespan in several animal models. Furthermore, clinical studies have shown that the blood vitamin C levels are lower in middle-aged and older adults than in younger adults. Lower blood vitamin C levels have also been observed in various pathological conditions such as chronic kidney disease and chronic obstructive pulmonary disease in the elderly. These observations suggest the implications of vitamin C in age-related pathological mechanisms owing to its physiological functions.

Keywords:  Age-related diseases; L-ascorbic acid; Lifespan; Vitamin C; Vitamin C-deficient models

DOI:  https://doi.org/10.1186/s12576-024-00922-7
ACS Omega. 2025 Jan 14. 10(1): 1519-1530

Production, Isolation, and Characterization of Stable Isotope-Labeled Standards for Mass Spectrometric Measurements of Oxidatively-Damaged Nucleosides in RNA.

Pawel Jaruga, Melis Kant, Miral Dizdaroglu.

RNA undergoes oxidatively induced damage in living organisms analogous to DNA. RNA is even more vulnerable to damage than DNA due to its greater abundance, single-strandedness, lack of repair and chromatin proteins shield, and instability, among other effects. RNA damage can adversely affect gene expression, leading to protein synthesis alterations, cell death, and other detrimental biological consequences. Growing indications suggest the involvement of oxidatively induced RNA damage in the pathogenesis of various human diseases, aging, and age-related diseases. Oxidatively induced damage can cause modifications to all four heterocyclic bases in RNA. Precise measurement of such modifications in RNA is essential for understanding the biological effects of oxidatively induced RNA damage. In the past, mass spectrometry has been used for this purpose. In mass spectrometric measurements, the use of stable isotope-labeled analogues of analytes as internal standards is essential for accurate quantifications. Past work utilized a stable isotope-labeled analogue of 8-hydroxyguanosine only as an internal standard. Thus, far, no stable isotope-labeled analogues of other oxidatively modified RNA nucleosides were available. In the present work, we report on the preparation, isolation, and characterization of the 13C- and 15N-labeled analogues of a variety of modified pyrimidine- and purine-derived RNA nucleosides. We also show the application of these internal standards for the measurement of oxidatively induced RNA damage in several commercially available RNA samples and in DNA along with DNA damage.

DOI: https://doi.org/10.1021/acsomega.4c09310
Brain Sci. 2024 Dec 24. pii: 6. [Epub ahead of print]15(1):

Age-Related Decline in Disengaging Spatial Attention in Physiological Aging.

Tiziana Pedale, Serena Mastroberardino, Nicola Tambasco, Valerio Santangelo.

  Background/Objectives: Attention is a complex process involving various components such as alerting, orienting, and resolving conflicts. These components have been widely examined using the Attention Network Test (ANT), which has also been used to explore attentional decline associated with aging. However, discrepancies exist in the literature regarding which specific aspects of attention are most impacted by aging. These inconsistencies could be due to methodological issues such as group comparisons that may exaggerate differences between groups while flattening subtle variations within groups. Methods: To address this issue, we administered the ANT to 60 healthy participants aged between 62 and 90 years. Using a multivariate regression analysis, we examined whether increasing age was associated with changes in alerting, orienting, and conflict resolution, while controlling for overall performance in terms of both reaction times and accuracy. Results: The results showed a general and age-insensitive decline in two of the three attentional components: the alerting effect, which was abolished, and a large conflict effect, which was present regardless of age. In contrast, the orienting of spatial attention was found to linearly increase with increasing age. More focused analyses revealed that the ability to shift attention from the central (initial) to the peripheral (target) location slowed down as a function of age. Conclusions: These results suggest that aging is associated with a greater difficulty in disengaging endogenous attention from the central, uninformative cue to direct attention on task-relevant peripheral targets.

Keywords:  aging; alerting; attention; conflict; executive function; orienting

DOI:  https://doi.org/10.3390/brainsci15010006
Epigenetics. 2025 Dec;20(1): 2451495

Timing of dietary effects on the epigenome and their potential protective effects against toxins.

Lynnea A Nicholls, Kendall A Zeile, London D Scotto, Rebecca J Ryznar.

  Exposure to toxins causes lasting damaging effects on the body. Numerous studies in humans and animals suggest that diet has the potential to modify the epigenome and these modifications can be inherited transgenerationally, but few studies investigate how diet can protect against negative effects of toxins. Potential evidence in the primary literature supports that caloric restriction, high-fat diets, high protein-to-carbohydrate ratios, and dietary supplementation protect against environmental toxins and strengthen these effects on their offspring's epigenome. Most notably, the timing when dietary interventions are given - during a parent's early development, pregnancy, and/or lifetime - result in similar transgenerational epigenetic durations. This implies the existence of multiple opportunities to strategically fortify the epigenome. This narrative review explores how to best utilize dietary modifications to modify the epigenome to protect future generations against negative health effects of persistent environmental toxins. Furthermore, by suggesting an ideal diet with specific micronutrients, macronutrients, and food groups, epigenetics can play a key role in the field of preventive medicine. Based on these findings, longitudinal research should be conducted to determine if a high protein, high-fat, and low-carbohydrate diet during a mother's puberty or pregnancy can epigenetically protect against alcohol, tobacco smoke, and air pollution across multiple generations.

Keywords:  DNA methylation; Epigenetic modifications; HDAC; dietary protection; environmental toxins; epigenetic duration; miRNA; transgenerational effects

DOI:  https://doi.org/10.1080/15592294.2025.2451495
Nat Commun. 2025 Jan 21. 16(1): 893

OGG1 and MUTYH repair activities promote telomeric 8-oxoguanine induced senescence in human fibroblasts.

Mariarosaria De Rosa, Ryan P Barnes, Ariana C Detwiler, Prasanth R Nyalapatla, Peter Wipf, Patricia L Opresko.

Telomeres are hypersensitive to the formation of the common oxidative lesion 8-oxoguanine (8oxoG), which impacts telomere stability and function. OGG1 and MUTYH glycosylases initiate base excision repair (BER) to remove 8oxoG or prevent mutation. Here, we show OGG1 loss or inhibition, or MUTYH loss, partially rescues telomeric 8oxoG-induced premature senescence and associated proinflammatory responses, while loss of both glycosylases causes a near complete rescue in human fibroblasts. Glycosylase deficiency also suppresses 8oxoG-induced telomere fragility and dysfunction, indicating that downstream single-stranded break (SSB) repair intermediates impair telomere replication. Preventing BER initiation suppresses PARylation and confers resistance to the synergistic effects of PARP inhibitors on 8oxoG-induced senescence. However, OGG1 activity is essential for preserving cell growth after chronic telomeric 8oxoG formation, whereas MUTYH promotes senescence to prevent chromosomal instability from unrepaired damage. Our studies reveal that inefficient completion of 8oxoG BER at telomeres triggers cellular senescence via SSB intermediates which disrupt telomere function.

DOI: https://doi.org/10.1038/s41467-024-55638-4
Front Mol Biosci. 2024 ;11 1524978

Irisin reshapes bone metabolic homeostasis to delay age-related osteoporosis by regulating the multipotent differentiation of BMSCs via Wnt pathway.

Shangman Xing, Yifan Ma, Bing Song, Min Bai, Kexin Wang, Wenjing Song, Tingting Cao, Chao Guo, Yanying Zhang, Zhandong Wang, Yongfeng Wang.

   Introduction: Bone aging is linked to changes in the lineage differentiation of bone marrow stem cells (BMSCs), which show a heightened tendency to differentiate into adipocytes instead of osteoblasts. The therapeutic potential of irisin in addressing age-related diseases has garnered significant attention. More significantly, irisin has the capacity to enhance bone mass recovery and sustain overall bone health. Its mechanism of action in preventing osteoporosis has generated considerable interest within the research community. Nonetheless, the targeting effect of irisin on age-related osteoporosis and its underlying molecular biological mechanisms remain unclear.
Methods: The specific role of irisin in osteogenic-adipogenic differentiation in young or aging BMSCs was evaluated by multiple cells staining and quantitative real-time PCR (RT-qPCR) analysis. RNA-seq and protein Western blotting excavated and validated the key pathway by which irisin influences the fate determination of aging BMSCs. The macroscopic and microscopic changes of bone tissue in aging mice were examined using Micro-computed tomography (Micro-CT) and morphological staining.
Results: It was noted that irisin affected the multilineage differentiation of BMSCs in a manner dependent on the dosage. Simultaneously, the Wnt signaling pathway might be a crucial mechanism through which irisin sustains the bone-fat balance in aging BMSCs and mitigates the decline in pluripotency. In vivo, irisin reduced bone marrow fat deposition in aging mice and effectively alleviating the occurrence of bone loss.
Conclusion: Irisin mediates the Wnt signaling pathway, thereby influencing the fate determination of BMSCs. In addition, it is essential for preserving metabolic equilibrium in the bone marrow microenvironment and significantly contributes to overall bone health. The findings provide new evidence for the use of iris extract in the treatment of age-related osteoporosis.

Keywords:  BMSCs; age-related osteoporosis; aging; bone-fat balance; irisin

DOI:  https://doi.org/10.3389/fmolb.2024.1524978
Tissue Eng Regen Med. 2025 Jan 18.

∆9-Tetrahydrocannabinol Increases Growth Factor Release by Cultured Adipose Stem Cells and Adipose Tissue in vivo.

Tim Ruhl, Sofija Benic, Melissa Plum, Bong-Sung Kim, Justus P Beier, Benedikt Schaefer.

   BACKGROUND: Because of its biocompatibility and its soft and dynamic nature, the grafting of adipose tissue is regarded an ideal technique for soft-tissue repair. The adipose stem cells (ASCs) contribute significantly to the regenerative potential of adipose tissue, because they can differentiate into adipocytes and release growth factors for tissue repair and neovascularization to facilitate tissue survival. The present study tested the effect of administering a chronic low dose of ∆9-tetrahydrocannabinol (THC) on these regenerative properties, in vitro and in vivo.
METHODS: Human ASCs were exposed to increasing concentrations of THC. Resazurin conversion was applied to investigate the effect on metabolic activity, cell number was assessed by crystal violet staining, tri-linear differentiation was evaluated by specific colorimetric approaches, and the release of growth factors was analyzed by ELISA. Two groups of mice were treated daily either with a low dose of THC (3 mg/kg) or a vehicle solution. After 3 weeks, adipose tissue was obtained from excised fat deposits, homogenized and tested for growth factor contents.
RESULTS: THC decreased ASC proliferation but increased metabolic activity as well as adipogenic and chondrogenic differentiation. A low concentration of THC (1 µM) enhanced the growth factor release by ASCs. The concentration of these cytokines was also increased in adipose tissue of mice treated with THC.
CONLUSION: Our results indicate that chronic activation of the endocannabinoid system promoted differentiation and growth factor release of ASCs, which could be of specific value for enhancing the regenerative potential of adipose tissue.

Keywords:  Cannabinoids; Regenerative properties; Stroma cells

DOI:  https://doi.org/10.1007/s13770-024-00692-8
Pharmacol Ther. 2025 Jan 16. pii: S0163-7258(25)00010-5. [Epub ahead of print] 108798

Unfolded protein responses: Dynamic machinery in wound healing.

Morgan Minjares, Pattaraporn Thepsuwan, Kezhong Zhang, Jie-Mei Wang.

  Skin wound healing is a dynamic process consisting of multiple cellular and molecular events that must be tightly coordinated to repair the injured tissue efficiently. The healing pace is decided by the type of injuries, the depth and size of the wounds, and whether wound infections occur. However, aging, comorbidities, genetic factors, hormones, and nutrition also impact healing outcomes. During wound healing, cells undergo robust processes of synthesizing new proteins and degrading multifunctional proteins. This imposes an increasing burden on the endoplasmic reticulum (ER), causing ER stress. Unfolded protein response (UPR) represents a collection of highly conserved stress signaling pathways originated from the ER to maintain protein homeostasis and modulate cell physiology. UPR is known to be beneficial for tissue healing. However, when excessive ER stress exceeds ER's folding potential, UPR pathways trigger cell apoptosis, interrupting tissue regeneration. Understanding how UPR pathways modulate the skin's response to injuries is critical for new interventions toward the control of acute and chronic wounds. Herein, in this review, we focus on the participation of the canonical and noncanonical UPR pathways during different stages of wound healing, summarize the available evidence demonstrating UPR's unique position in balancing homeostasis and pathophysiology of healing tissues, and highlight the understudied areas where therapeutic opportunities may arise.

Keywords:  Endoplasmic reticulum; Gene therapy; Unfolded protein response; Wound healing

DOI:  https://doi.org/10.1016/j.pharmthera.2025.108798
Noncoding RNA. 2025 Jan 09. pii: 2. [Epub ahead of print]11(1):

LncRNA 3222401L13Rik Is Upregulated in Aging Astrocytes and Regulates Neuronal Support Function Through Interaction with Npas3.

Sophie Schröder, M Sadman Sakib, Dennis M Krüger, Tonatiuh Pena, Susanne Burkhardt, Anna-Lena Schütz, Farahnaz Sananbenesi, André Fischer.

  Aging leads to cognitive decline and increased risk of neurodegenerative diseases. While molecular changes in central nervous system (CNS) cells contribute to this decline, the mechanisms are not fully understood. Long non-coding RNAs (lncRNAs) are key regulators of cellular functions. Background/Objectives: The roles of lncRNAs in aging, especially in glial cells, are not well characterized. Methods: We investigated lncRNA expression in non-neuronal cells from aged mice and identified 3222401L13Rik, a previously unstudied lncRNA, as upregulated in astrocytes during aging. Results: Knockdown of 3222401L13Rik in primary astrocytes revealed its critical role in regulating genes for neuronal support and synapse organization, a function conserved in human iPSC-derived astrocytes. A 3222401L13Rik interacts with the transcription factor Neuronal PAS Domain Protein 3 (Npas3), and overexpression of Npas3 rescues deficits in astrocytes lacking 3222401L13Rik. Conclusions: These data suggest that 3222401L13Rik upregulation may help delay age-related cognitive decline.

Keywords:  Alzheimer’s disease; aging; astrocytes; brain; lncRNA; neurodegenerative diseases; non-coding RNA; transcriptomics

DOI:  https://doi.org/10.3390/ncrna11010002
Free Radic Biol Med. 2025 Jan 17. pii: S0891-5849(25)00038-3. [Epub ahead of print]

Intestine-specific disruption of mitochondrial superoxide dismutase extends longevity.

Thomas Liontis, Megan M Senchuk, Shusen Zhu, Suleima Jacob-Tomas, Ulrich Anglas, Annika Traa, Sonja K Soo, Jeremy M Van Raamsdonk.

  Reactive oxygen species (ROS) are highly reactive oxygen containing molecules that are generated by normal metabolism. While ROS can cause damage to the building blocks that make up cells, these molecules can also act as intracellular signals that promote longevity. The levels of ROS within the cell can be regulated by antioxidant enzymes, such as superoxide dismutase (SOD), which converts superoxide to hydrogen peroxide. Interestingly, our previous work has shown that disruption of the mitochondrial SOD gene sod-2 results in increased lifespan, suggesting that elevating levels of mitochondrial superoxide can promote longevity. To explore the molecular mechanisms involved, we determined the tissues in which disruption of sod-2 is necessary for lifespan extension and the tissues in which disruption of sod-2 is sufficient to extend lifespan. We found that tissue-specific restoration of SOD-2 expression in worms lacking SOD-2 could partially revert changes in fertility, embryonic lethality and resistance to stress, but did not inhibit the effects of sod-2 deletion on lifespan. Knocking down sod-2 expression using RNA interference specifically in the intestine, but not other tissues, was sufficient to extend longevity. Intestine-specific knockdown of sod-2 also increased resistance to heat stress while decreasing resistance to oxidative stress. Combined, these results indicate that disruption of sod-2 in neurons, intestine, germline, or muscle is not required for lifespan extension, but that decreasing sod-2 expression in just the intestine extends lifespan. This work defines the conditions required for disruption of mitochondrial superoxide dismutase to increase longevity.

Keywords:  Aging; C. elegans; genetics; mitochondria; reactive oxygen species; superoxide dismutase; tissue specificity

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.01.032
Biogerontology. 2025 Jan 20. 26(1): 46

The interplay of senescence and MMPs in myocardial infarction: implications for cardiac aging and therapeutics.

Ashok Kumar Balaraman, Abdulmalik Saleh Alfawaz Altamimi, M Arockia Babu, Kavita Goyal, G PadmaPriya, Pooja Bansal, Sumit Rajotiya, M Ravi Kumar, Pranchal Rajput, Mohd Imran, Gaurav Gupta, Lakshmi Thangavelu.

  Aging is associated with a marked increase in cardiovascular diseases, such as myocardial infarction (MI). Cellular senescence is also a crucial factor in the development of age-related MI. Matrix metalloproteinases (MMPs) interaction with cellular senescence is a critical determinant of MI development and outcomes, most notably in the aged heart. After experiencing a heart attack, senescent cells exhibit a Senescence-Associated Secretory Phenotype (SASP) and are involved in tissue regeneration and chronic inflammation. MMPs are necessary for extracellular matrix proteolysis and have a biphasic effect, promoting early heart healing and detrimental change if overexpressed shortly. This review analyses the complex connection between senescence and MMPs in MI and how it influences elderly cardiac performance. Critical findings suggest that increasing cellular senescence in aged hearts elevates MMP activity and aggravates extended ventricular remodeling and dysfunction. Additionally, we explore potential therapeutics that address MMPs and senescence to enhance old MI patient myocardial performance and regeneration.

Keywords:  Aging hearts; Cellular senescence; MMP regulation; Matrix metalloproteinases; Myocardial infarction; SASP

DOI:  https://doi.org/10.1007/s10522-025-10190-6
J Mol Biol. 2025 Jan 16. pii: S0022-2836(25)00017-8. [Epub ahead of print] 168951

Biomolecular Condensates in Telomere Maintenance of ALT Cancer Cells.

Xiaoyang Yu, Huaiying Zhang.

  Alternative Lengthening of Telomeres (ALT) pathway is a telomerase-independent mechanism that utilizes homology-directed repair (HDR) to sustain telomere length in specific cancers. Biomolecular condensates, such as ALT-associated promyelocytic leukemia nuclear bodies (APBs), have emerged as critical players in the ALT pathway, supporting telomere maintenance in ALT-positive cells. These condensates bring together DNA repair proteins, telomeric repeats, and other regulatory elements. By regulating replication stress and promoting DNA synthesis, ALT condensates create an environment conducive to HDR-based telomere extension. This review explores recent advancements in ALT, focusing on understanding the role of biomolecular condensates in ALT and how they impact telomere dynamics and stability.

Keywords:  ALT cancer; Biomolecular Condensate; DNA repair; Phase separation; telomere

DOI:  https://doi.org/10.1016/j.jmb.2025.168951
Front Aging Neurosci. 2024 ;16 1473178

Spontaneous blinking and brain health in aging: Large-scale evaluation of blink-related oscillations across the lifespan.

Cam-CAN Group

  Blink-related oscillations (BROs) are newly discovered neurophysiological brainwave responses associated with spontaneous blinking, and represent environmental monitoring and awareness processes as the brain evaluates new visual information appearing after eye re-opening. BRO responses have been demonstrated in healthy young adults across multiple task states and are modulated by both task and environmental factors, but little is known about this phenomenon in aging. To address this, we undertook the first large-scale evaluation of BRO responses in healthy aging using the Cambridge Centre for Aging and Neuroscience (Cam-CAN) repository, which contains magnetoencephalography (MEG) data from a large sample (N = 457) of healthy adults across a broad age range (18-88) during the performance of a simple target detection task. The results showed that BRO responses were present in all age groups, and the associated effects exhibited significant age-related modulations comprising an increase in sensor-level global field power (GFP) and source-level theta and alpha spectral power within the bilateral precuneus. Additionally, the extent of cortical activations also showed an inverted-U relationship with age, consistent with neurocompensation with aging. Crucially, these age-related differences were not observed in the behavioral measures of task performance such as reaction time and accuracy, suggesting that blink-related neural responses during the target detection task are more sensitive in capturing aging-related brain function changes compared to behavioral measures alone. Together, these results suggest that BRO responses are not only present throughout the adult lifespan, but the effects can also capture brain function changes in healthy aging-thus providing a simple yet powerful avenue for evaluating brain health in aging.

Keywords:  aging; blink-related oscillations (BROs); blinking; magnetoencephalography (MEG); neurophysiology and brainwaves; precuneus

DOI:  https://doi.org/10.3389/fnagi.2024.1473178
Sci Rep. 2025 Jan 21. 15(1): 2612

PLK3 weakens antioxidant defense and inhibits proliferation of porcine Leydig cells under oxidative stress.

Chujie Chen, Jinyan He, Weixian Huang, Dong Xu, Zhaohui Li, Anqi Yang.

  Aging is characterized by cellular degeneration and impaired physiological functions, leading to a decline in male sexual desire and reproductive capacity. Oxidative stress (OS) lead to testicular aging by impairing the male reproductive system, but the potential mechanisms remain unclear. In the present study, the functional status of testicular tissues from young and aged boars was compared, and the transcriptional responses of Leydig cells (LCs) to hydrogen peroxide (H2O2)-induced senescence were explored, revealing the role of OS in promoting aging of the male reproductive system. 601 differentially expressed genes (DEGs) associated with OS, cell cycle regulation, and intracellular processes were identified. These DEGs were significantly enriched in critical aging pathways, including the p53 signaling pathway, autophagy, and cellular senescence. Protein-protein interaction (PPI) network analysis unveiled 15 key genes related to cell cycle and DNA replication, with polo-like kinase 3 (PLK3) exhibiting increased expression under OS. In vitro, PLK3 knockdown significantly enhanced the viability and antioxidant capacity of LCs under OS. This study deepens our understanding of how LCs respond to OS and provides new therapeutic targets for enhancing cellular resistance to oxidative damage and promoting tissue health.

Keywords:   PLK3 ; Leydig cells; Oxidative stress; Transcriptome sequencing

DOI:  https://doi.org/10.1038/s41598-025-86867-2
Clin Exp Med. 2025 Jan 23. 25(1): 44

Cellular senescence in the tumor with a bone niche microenvironment: friend or foe?

Sajad Alavimanesh, Negar Nayerain Jazi, Maedeh Choubani, Farzane Saeidi, Hamed Afkhami, Aref Yarahmadi, Hossein Ronaghi, Pouria Khani, Mohammad Hossein Modarressi.

  Cellular senescence is understood to be a biological process that is defined as irreversible growth arrest and was originally recognized as a tumor-suppressive mechanism that prevents further propagation of damaged cells. More recently, cellular senescence has been shown to have a dual role in prevention and tumor promotion. Senescent cells carry a senescence-associated secretory phenotype (SASP), which is altered by secretory factors including pro-inflammatory cytokines, chemokines, and other proteases, leading to the alteration of the tissue microenvironment. Though senescence would eventually halt the growth of cancerous potential cells, SASP contributes to the tumor environment by promoting inflammation, matrix remodeling, and tumor cell invasion. The paradox of tumor prevention/promotion is particularly relevant to the bone niche tumor microenvironment, where longer-lasting, chronic inflammation promotes tumor formation. Insights into a mechanistic understanding of cellular senescence and SASP provide the basis for targeted therapies, such as senolytics, which aim to eliminate senescent cells, or SASP inhibitors, which would eliminate the tumor-promoting effects of senescence. These therapeutic interventions offer significant clinical implications for treating cancer and healthy aging.

Keywords:  Bone niche; Cellular senescence; Senescence-associated secretory phenotype (SASP); Tumor microenvironment

DOI:  https://doi.org/10.1007/s10238-025-01564-8