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Senescence in renal cells has attracted wide attention as the critical factor promoting renal fibrosis and chronic kidney disease. Establishing a reliable cellular model is essential to study mechanisms underlying renal cell senescence. Herein, we compared various inducers to define the most suitable senescence inducer for HK-2 proximal tubular cells. These inducers included hydrogen peroxide (H 2 O 2 ), high-temperature (HT), glucose, mannitol and hydroxyurea (HU). To screen for optimal concentration/level, the highest concentration/level of each inducer that did not increase cell death (to avoid severe toxicity) was selected for senescence induction and comparative analysis using the two most appropriate markers for HK-2 cell senescence as recently established. The data revealed that 0.4 mM, 43 °C, 80 mM, 80 mM and 100 μM were the optimal concentrations/levels of H 2 O 2 , HT, glucose, mannitol and HU, respectively. Comparative analysis using optimal concentration/level of each marker revealed that 0.4 mM H 2 O 2 , HT at 43 °C, 80 mM glucose and 80 mM mannitol were the weak senescence inducers. The most effective inducer for HK-2 senescence was 100 μM HU, which provided the greatest fold-changes of cell area and granularity when compared with other stimuli in a time-dependent manner. Based on these data comparing H 2 O 2 , HT, glucose, mannitol and HU at their optimal concentrations/levels, 100 μM HU seems to be most effective for senescence induction in HK-2 cells for in vitro study of proximal renal tubular cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) and leading to cellular senescence and cognitive deficits. Cellular senescence contributes significantly to the pathogenesis of AD through the senescence-associated secretory phenotype (SASP), exacerbating Aβ deposition. This study investigates the protective effects of 3-N-Butylphthalide (NBP), a compound derived from Apium graveolens Linn (Chinese celery), on Aβ-induced cellular senescence in U87 cells. Using RNA-sequencing and biochemical assays, we demonstrate that NBP ameliorate Aβ oligomer-induced cellular senescence and apoptosis, and regulated the expression of cyclin-dependent kinase inhibitor 2A (CDKN2A) and components of the cyclin-dependent kinase 2 (CDK2)- phosphorylated retinoblastoma 1 (pRB1)-Caspase3 pathway. Moreover, NBP was shown to suppress the expression of SASP-related genes. These findings suggest that NBP rescues U87 cells from Aβ oligomer-induced senescence and apoptosis through modulating the CDK2-pRB1-Caspase3 axis and SASP expression. Our results underscore the potential of NBP as a senostatic agent for AD which have not been reported in previous studies, offering insights into its mechanisms of action and paving the way for future studies on its efficacy in vivo and in clinical settings. Thus, we contribute to growing evidence supporting the use of senolytic and senostatic agents in the treatment of AD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Healthy aging is a common goal for humanity and society, and one key to achieving it is the rejuvenation of senescent resident stem cells and empowerment of aging organ regeneration. However, the mechanistic understandings of stem cell senescence and the potential strategies to counteract it remain elusive. Here, we reveal that the aging bone microenvironment impairs the Golgi apparatus thus diminishing mesenchymal stem cell (MSC) function and regeneration. Interestingly, replenishment of cell aggregates-derived extracellular vesicles (CA-EVs) rescues Golgi dysfunction and empowers senescent MSCs through the Golgi regulatory protein Syntaxin 5. Importantly, in vivo administration of CA-EVs significantly enhanced the bone defect repair rate and improved bone mass in aging mice, suggesting their therapeutic value for treating age-related osteoporosis and promoting bone regeneration. Collectively, our findings provide insights into Golgi regulation in stem cell senescence and bone aging, which further highlight CA-EVs as a potential rejuvenative approach for aging bone regeneration., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Aging is a physiological/pathological process accompanied by progressive impairment of cellular function, leading to a variety of aging-related diseases. STAT3 is one of the core regulatory factors of aging. It is involved in body metabolism, development and senescence, cell apoptosis and so on. During the aging process, the changes of growth factors and cytokines will cause the activation of STAT3 to varying degrees, regulate the inflammatory pathways related to aging, regulate body inflammation, mitochondrial function, cell aging and autophagy to regulate and influence the aging process. Drugs targeting STAT3 can treat senescence related diseases. This review summarizes the role of STAT3 signaling factors in the pathogenesis of aging, including mitochondrial function, cellular senescence, autophagy, and chronic inflammation mediated by inflammatory pathways. Finally, the key regulatory role of STAT3 in senescence related diseases is emphasized. In summary, we reveal that drug development and clinical application targeting STAT3 is one of the key points in delaying aging and treating aging-related diseases in the future., Competing Interests: Declarations. Conflicts of interest: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature B.V.)

Oncogenic types of human papillomaviruses (HPVs) are major human carcinogens. The formation of a trimeric complex between the HPV E6 oncoprotein, the cellular ubiquitin ligase E6AP and the p53 tumor suppressor protein leads to proteolytic p53 degradation and plays a central role for HPV-induced cell transformation. We here uncover that E6AP silencing in HPV-positive cancer cells ultimately leads to efficient induction of cellular senescence, revealing that E6AP acts as a potent anti-senescent factor in these cells. Thus, although the downregulation of either E6 or E6AP expression also acts partially pro-apoptotic, HPV-positive cancer cells surviving E6 repression proliferate further, whereas they become irreversibly growth-arrested upon E6AP repression. We moreover show that the senescence induction following E6AP downregulation is mechanistically highly dependent on induction of the p53/p21 axis, other than the known pro-senescent response of HPV-positive cancer cells following combined downregulation of the viral E6 and E7 oncoproteins. Of further note, repression of E6AP allows senescence induction in the presence of the anti-senescent HPV E7 protein. Yet, despite these mechanistic differences, the pathways underlying the pro-senescent effects of E6AP or E6/E7 repression ultimately converge by being both dependent on the cellular pocket proteins pRb and p130. Taken together, our results uncover a hitherto unrecognized and potent anti-senescent function of the E6AP protein in HPV-positive cancer cells, which is essential for their sustained proliferation. Our results further indicate that interfering with E6AP expression or function could result in therapeutically desired effects in HPV-positive cancer cells by efficiently inducing an irreversible growth arrest. Since the critical role of the E6/E6AP/p53 complex for viral transformation is conserved between different oncogenic HPV types, this approach could provide a therapeutic strategy, which is not HPV type-specific., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Avenhaus et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Neuroinflammation is closely linked to aging, which damages the structure and function of the brain. It is caused by the intricate interactions of immune cells in the aged brain, such as the dysregulated glial cells and the dysfunctional astrocytes. Aging-associated chronic low inflammation, referred to as neuroinflammaging, shows an upregulated proinflammatory response. Autophagy and senescence play crucial roles as moderators of aging and neuroinflammatory responses. The dysregulated neuroimmune system, dystrophic glial cells, and release of proinflammatory factors alter blood-brain barrier, causing a neuroinflammatory landscape. Chronic inflammation combined with deteriorating neurons exacerbate neurological disorders and decline in cognitive function. This review highlights the neuroinflammaging and mechanism associated with immune cells interplay with central nervous system and aging, cellular senescence, and autophagy regulation in the brain's immune system under neuroinflammatory conditions. Moreover, the roles of microglia and peripheral immune cells in the neuroinflammatory process in the aging brain have also been discussed. Determining treatment targets and comprehending mechanisms that influence immune cells in the aged brain is necessary to decrease neuroinflammation., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Cellular senescence, a hallmark of aging, has been implicated in Alzheimer's disease (AD) pathogenesis. Cholesterol accumulation is known to drive cellular senescence; however, its underlying mechanisms are not fully understood. ATP-binding cassette transporter A1 (ABCA1) plays an important role in cholesterol homeostasis, and its expression and trafficking are altered in APOE4 and AD models. However, the role of ABCA1 trafficking in cellular senescence associated with APOE4 and AD remains unclear., Methods: We examined the association between cellular senescence and ABCA1 expression in human postmortem brain samples using transcriptomic, histological, and biochemical analyses. Unbiased proteomic screening was performed to identify the proteins that mediate cellular ABCA1 trafficking. We created ABCA1 knock out cell lines and mouse models to validate the role of ABCA1 in cholesterol-induced mTORC1 activation and senescence. Additionally, we used APOE4-TR mice and induced pluripotent stem cell (iPSC) models to explore cholesterol-ABCA1-senescence pathways., Results: Transcriptomic profiling of the human dorsolateral prefrontal cortex from the Religious Order Study/Memory Aging Project (ROSMAP) cohort revealed the upregulation of cellular senescence transcriptome signatures in AD, which correlated with ABCA1 expression and oxysterol levels. Immunofluorescence and immunoblotting analyses confirmed increased lipofuscin-stained lipids and ABCA1 expression in AD brains and an association with mTOR phosphorylation. Discovery proteomics identified caveolin-1, a sensor of cellular cholesterol accumulation, as a key promoter of ABCA1 endolysosomal trafficking. Greater caveolin-1 expression was observed in APOE4-TR mouse models and AD human brains. Oxysterol induced mTORC1 activation and senescence were regulated by ABCA1 lysosomal trapping. Treatment of APOE4-TR mice with cyclodextrin reduced brain oxysterol levels, ABCA1 lysosome trapping, mTORC1 activation, and attenuated senescence and neuroinflammation markers. In human iPSC-derived astrocytes, the reduction of cholesterol by cyclodextrin attenuated inflammatory responses., Conclusions: Oxysterol accumulation in APOE4 and AD induced ABCA1 and caveolin-1 expression, contributing to lysosomal dysfunction and increased cellular senescence markers. This study provides novel insights into how cholesterol metabolism accelerates features of brain cellular senescence pathway and identifies therapeutic targets to mitigate these processes., Competing Interests: Declaration. Competing interests: The authors declare that they have no conflicts of interest., (© 2025. The Author(s).)

Adult stem cells maintain homeostasis and enable regeneration of most tissues. Quiescence, proliferation, and differentiation of stem cells and their progenitors are tightly regulated processes governed by dynamic transcriptional, epigenetic, and metabolic programs. Previously thought to merely reflect a cell's energy state, metabolism is now recognized for its critical regulatory functions, controlling not only energy and biomass production but also the cell's transcriptome and epigenome. In this review, we explore how metabolic pathways, metabolites, and transcriptional and epigenetic regulators are functionally interlinked in adult and aging skeletal muscle stem cells., (Published by Cold Spring Harbor Laboratory Press.)

Senescent retinal pigment epithelial cells play a key role in neovascular age-related macular degeneration (nAMD); however, the mechanisms underlying the angiogenic ability of these cells remain unclear. Herein, we investigated the effects of the senescent adult retinal pigment epithelial cell line-19 (ARPE-19) on wound healing, cell migration and survival, and tube formation abilities of human umbilical vein endothelial cells (HUVECs). Additionally, we used Brown Norway rats to establish a laser-induced choroidal neovascularization (CNV) model for further nAMD-related studies. We found that the wound healing, cell migration, and tube formation abilities of HUVECs were significantly enhanced following culture in conditioned media from senescent ARPE-19 cells; this was attributed to the activation of the transforming growth factor β-activated kinase 1 (TAK1)/p38 MAPK pathway. Consistently, we found that the TAK1 inhibitors 5Z-7-oxozeaenol and takinib reversed the effects of conditioned media from senescent ARPE-19 cells on the wound healing, migration, survival, and tube formation abilities of HUVECs. We further investigated the therapeutic effects of 5Z-7-oxozeaenol on the laser-induced CNV rat model. We found that TAK1 was activated in IB4+ areas in laser-induced CNV lesions; inhibiting the activity of TAK1 using 5Z-7-oxozeaenol significantly alleviated CNV lesion formation and fluorescein leakage in fundus fluorescein angiography and greatly improved a-waves, b-waves, and OP values, as recorded by electroretinography. Thus, senescent RPE cells may promote angiogenesis via the TAK1/p38 MAPK pathway. Further, inhibiting TAK1 expression alleviates pathological neovascularization and improves retinal function in a laser-induced CNV rat model, highlighting the therapeutic potential of this approach for treating nAMD., Competing Interests: Declaration of interest The authors declare that they have no competing interests., (Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Cellular senescence, a complex biological process resulting in permanent cell-cycle arrest, is central to aging and age-related diseases. A key concept in understanding cellular senescence is the Hayflick Limit, which refers to the limited capacity of normal human cells to divide, after which they become senescent. Senescent cells (SC) accumulate with age, releasing pro-inflammatory and tissue-remodeling factors collectively known as the senescence-associated secretory phenotype (SASP). The causes of senescence are multifaceted, including telomere attrition, oxidative stress, and genotoxic damage, and they extend to influences from microbial sources. Research increasingly emphasizes the role of the microbiome, especially gut microbiota (GM), in modulating host senescence processes. Beneficial microbial metabolites, such as short-chain fatty acids (SCFAs), support host health by maintaining antioxidant defenses and reducing inflammation, potentially mitigating senescence onset. Conversely, pathogenic bacteria like Pseudomonas aeruginosa and Helicobacter pylori introduce factors that damage host DNA or increase ROS, accelerating senescence via pathways such as NF-κB and p53-p21. This review explores the impact of bacterial factors on cellular senescence, highlighting the role of specific bacterial toxins in promoting senescence. Additionally, it discusses how dysbiosis and the loss of beneficial microbial species further contribute to age-related cellular deterioration. Modulating the gut microbiome to delay cellular senescence opens a path toward targeted anti-aging strategies. This work underscores the need for deeper investigation into microbial influence on aging, supporting innovative interventions to manage and potentially reverse cellular senescence., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

In this review, we review the current status of biomarkers for aging and possible perspectives on anti-aging or rejuvenation from the standpoint of biomarkers. Aging is observed in all cells and organs, and we focused on research into senescence in the skin, musculoskeletal system, immune system, and cardiovascular system. Commonly used biomarkers include SA-βgal, cell-cycle markers, senescence-associated secretory phenotype (SASP) factors, damage-associated molecular patterns (DAMPs), and DNA-damage-related markers. In addition, each organ or cell has its specific markers. Generally speaking, a combination of biomarkers is required to define age-related changes. When considering the translation of basic research, biomarkers that are highly sensitive, highly specific, with validation and reliability as well as being non-invasive are optimal; however, currently reported markers do not fulfill the prerequisite for biomarkers. In addition, rodent models of aging do not necessarily represent human aging, and markers in rodent or cell models are not applicable in clinical settings. The prerequisite of clinically applicable biomarkers is that they provide useful information for clinical decision-making, such as predicting disease risk, diagnosing disease, monitoring disease progression, or guiding treatment decisions. Therefore, the development of non-invasive robust, reliable, and useful biomarkers in humans is necessary to develop anti-aging therapy for humans. Geriatr Gerontol Int 2025; 25: 139-147., (© 2025 Japan Geriatrics Society.)

Molecular mechanisms of aging processes at the level of organisms and cells are in the focus of a large number of research laboratories. This research culminated in recent breakthroughs, which contributed to the better understanding of the natural aging process and aging associated malfunctions leading to age-related diseases. Ca 2+ in connection with its master intracellular sensor protein calmodulin (CaM) regulates a plethora of crucial cellular processes orchestrating a wide range of signaling processes. This review focuses on the involvement of Ca 2+ /CaM in cellular mechanisms, which are associated with normal aging, as well as playing a role in the development of diseases connected with signaling processes during aging. We specifically highlight processes that involve inactivation of proteins, which take part in Ca 2+ /CaM regulatory systems by oxygen or nitrogen free radical species, during organismal aging and cellular senescence. As examples of organs where aging processes have recently been investigated, we chose to review the literature on molecular aging processes with involvement of Ca 2+ /CaM in heart and neuronal diseases, as well as in cancer and metabolic diseases, all deeply affected by aging. In addition, this article focuses on cellular senescence, a mechanism that may contribute to aging processes and therefore has been proposed as a target to interfere with the progression of age-associated diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

During the last few decades, life expectancy has increased worldwide along with the prevalence of several age-related diseases. Among aging pathways, cellular senescence and chronic inflammation (or "inflammaging") appear to be connected to gut homeostasis and dysbiosis of the microbiome. Cellular senescence is a state of essentially irreversible cell cycle arrest that occurs in response to stress. Although senescent cells (SC) remain metabolically active, they do not proliferate and can secrete inflammatory and other factors comprising the senescence-associated secretory phenotype (SASP). Accumulation of SCs has been linked to onset of several age-related diseases, in the brain, bones, the gastrointestinal tract, and other organs and tissues. The gut microbiome undergoes substantial changes with aging and is tightly interconnected with either successful (healthy) aging or disease. Senotherapeutic drugs are compounds that can clear senescent cells or modulate the release of SASP factors and hence attenuate the impact of the senescence-associated pro-inflammatory state. Phytochemicals, phenolic compounds and terpenes, which have antioxidant and anti-inflammatory activities, could also be senotherapeutic given their ability to act upon senescence-linked cellular pathways. The aim of this review is to dissect links among the gut microbiome, cellular senescence, inflammaging, and disease, as well as to explore phytochemicals as potential senotherapeutics, focusing on their interactions with gut microbiota. Coordinated targeting of these inter-related processes might unveil new strategies for promoting healthy aging., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: The mechanism behind abnormal placental aging in preeclampsia (PE) is unclear. Although TIG1 is widely expressed in the human placenta, its function hasn't been well understood. Our previous study found a significant elevation of TIG1 in the placentas of PE patients. In this study, we focused on the molecular mechanism by which TIG1 functions in PE., Methods: TIG1 expression of placentas from PE patients and L-NAME mice were analyzed using qRT-PCR, Western blot, and immunohistochemistry. TIG1-overexpressed HTR-8/SVneo cells were constructed for transcriptomic sequencing. Senescence in the placenta was evaluated by biomarkers of p16, p21, and p53. TIG1 binding proteins were identified via co-immunoprecipitation. A co-culture system of HTR-8/SVneo and human endometrial stromal cells was developed to study the change in trophoblasts' function., Results: TIG1 expression was significantly increased in the PE placentas. Elevated expression of TIG1 was associated with abnormal senescence of trophoblasts. TIG1 induced trophoblasts' senescence by regulating LMNA/p53 axis. The senescence of trophoblasts can be manifested as reduced invasion ability in the co-culture system., Discussion: Our study indicated that TIG1 was crucial in the development of PE by causing the senescence of trophoblasts and reducing their invasiveness, offering insights into the molecular mechanisms of placental dysfunction in PE., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Zhijian Wang, Qian Chen reports financial support was provided by the National Natural Science Foundation of China, the Natural Science Foundation of Guangdong Province. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease linked to aging. This study investigates potential connections between IPF and age-related eye problems using a bleomycin-induced IPF mouse model. Intratracheal administration of bleomycin induces rapid lung injury in mice, followed by IPF with characteristics of cellular senescence. IPF-injured mice had reduced amplitudes of scotopic ERG and immunostaining of visual arrestin, suggesting declined rod-related visual function. Interestingly, the mice's eyes also showed increased susceptibility to Staphylococcus aureus infections, reminiscent of the aging eyes. To determine whether an early onset of aging contributes to the eye disorders, we examined complement and senescence markers in the retina. In bleomycin-injury IPF mice, DNA damage-related senescence marker γH2AX was found in the retinal out nuclear layer where photoreceptors are located. Additionally, IPF mice displayed elevated levels of C3b, a complement fragment resulting from C3 activation that occurs frequently in aging eyes. These findings underscore the potential of IPF as a valuable mouse model for investigating early-onset age-related ocular disorders., Competing Interests: Declaration of competing interest The authors declare that there is no potential conflict of interest., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Melasma is an acquired chronic pigmentary disorder affecting millions of individuals worldwide. However, the pathogenesis of melasma remains unclear. This article provides a comprehensive review of the pathophysiological changes occurring in the skin microenvironment of melasma lesions, which can be summarized as follows: (1) skin barrier dysfunction and abnormal synthesis, transport, and intracellular distribution of melanin in the epidermis; (2) basement membrane damage; (3) solar elastosis, vascular changes, senescent fibroblasts, mast cell infiltration, and sebocyte participation in the dermis; and (4) systemic factors such as sex hormones and oxidative stress. Furthermore, potential therapeutic strategies are introduced to provide novel perspectives for fundamental and clinical research related to melasma., (© 2024 the International Society of Dermatology.)

Senescence and loss of cochlear hair cells is an important pathologic basis of age-related hearing loss. Lipid droplet accumulation has previously been shown to play an important role in neurodegeneration; however, its role in age-related hearing loss has not yet been investigated. LXRβ/ABCA1 is a key pathway that regulates lipid metabolism, while its dysfunction can cause abnormal accumulation of lipid droplets in neurons, leading to neurodegeneration. In this study, we found that decreased expression of LXRβ/ABCA1, elevated levels of lipid droplet accumulation, and increased activation of the NLRP3 inflammasome were demonstrated in senescent cochlear hair cells in both animal and cellular models of age-related hearing loss. We then manipulated the LXRβ/ABCA1 pathway transduction of cochlear hair cells. Upregulation of LXRβ/ABCA1 in senescent hair cells was found to reduce the accumulation of lipid droplets, inhibit NLRP3 inflammasome activation, and ultimately alleviate cochlear hair cell senescence. In our study, we also found that NLRP3 inflammasome activation can abrogate the alleviated effect of LXRβ/ABCA1 pathway on the senescence of cochlear hair cells but did not affect the expression of LXRβ/ABCA1.Our study are the first to demonstrate that abnormal lipid droplet accumulation and decreased LXRβ/ABCA1 pathway are observed in cochlear hair cells following the occurrence of age-related hearing loss. Upregulation of LXRβ/ABCA1 in senescent cochlear hair cells can reduce lipid droplet accumulation in cochlear hair cells and alleviate their senescence, which may be related to the inhibition of NLRP3 inflammasome activation. These findings provide potential targets for the treatment of age-related hearing loss., Competing Interests: Declarations. Conflict of interests: The authors declare no competing interests. Ethical approval: All procedures involving animals were approved by the Animal Care and Use Committee of Shanghai Jiao Tong University School of Medicine and that were consistent with the National Institute of Health’s Guide for the Care and Use of Laboratory Animals., (© 2025. The Author(s), under exclusive licence to Springer Nature B.V.)

A metabolic switch enables hepatocytes in damaged livers to escape senescence and form tumors.

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., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature B.V.)

The growing prevalence of age-related cardiovascular diseases (CVDs) poses significant health challenges, necessitating the formulation of novel treatment approaches. GATA4, a vital transcription factor identified for modulating cardiovascular biology and cellular senescence, is recognized for its critical involvement in CVD pathogenesis. This review collected relevant studies from PubMed, Google Scholar, and Science Direct using search terms like 'GATA4,' 'cellular senescence,' 'coronary artery diseases,' 'hypertension,' 'heart failure,' 'arrhythmias,' 'congenital heart diseases,' 'cardiomyopathy,' and 'cardiovascular disease.' Additionally, studies investigating the molecular mechanisms underlying GATA4-mediated regulation of GATA4 and senescence in CVDs were analyzed to provide comprehensive insights into this critical aspect of potential treatment targeting. Dysregulation of GATA4 is involved in a variety of CVDs, as demonstrated by both experimental and clinical research, comprising CAD, hypertension, congenital heart diseases, cardiomyopathy, arrhythmias, and cardiac insufficiency. Furthermore, cellular senescence enhances the advancement of age-related CVDs. These observations suggested that therapies targeting GATA4, senescence pathways, or both as necessary may be an effective intervention in CVD progression and prognosis. Addressing age-related CVDs by targeting GATA4 and senescence is a broad mechanism approach. It implies further investigation of the molecular nature of these processes and elaboration of an effective therapeutic strategy. This review highlights the importance of GATA4 and senescence in CVD pathogenesis, emphasizing their potential as therapeutic targets for age-related CVDs., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature B.V.)

Targeting cellular senescence and senescence associated secretory phenotype (SASP) through autophagy has emerged as a promising intervertebral disc (IVD) degeneration (IDD) treatment strategy in recent years. This study aimed to clarify the role and mechanism of autophagy in preventing IVD SASP. Methods involved in vitro experiments with nucleus pulposus (NP) tissues from normal and IDD patients, as well as an in vivo IDD animal model. GATA4's regulatory role in SASP was validated both in vitro and in vivo, while autophagy modulators were employed to assess their impact on GATA4 and SASP. Transcriptomic sequencing identified oxidized low-density lipoprotein receptor 1 (OLR1) as a key regulator of autophagy and GATA4. A series of experiments manipulated OLR1 expression to investigate associated effects. Results demonstrated significantly increased senescent NP cells (NPCs) and compromised autophagy in IDD patients and animal models, with SASP closely linked to IDD progression. The aged disc milieu impeded autophagic GATA4 degradation, leading to elevated SASP expression in senescent NPCs. Restoring autophagy reversed senescence by degrading GATA4, hence disrupting the SASP cascade. Moreover, OLR1 was identified for its regulation of autophagy and GATA4 in senescent NPCs. Silencing OLR1 enhanced autophagic activity, suppressing GATA4-induced senescence, and SASP expression in senescent NPCs. In conclusion, OLR1 was found to control autophagy-GATA4 and SASP, with targeted OLR1 inhibition holding promise in alleviating GATA4-induced senescence and SASP expression while delaying extracellular matrix degradation, offering a novel therapeutic approach for IDD management., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

As the healthcare burden caused by an increasingly aging population rapidly rises, a pressing need exists for innovative geroscience research that can elucidate aging mechanisms and precipitate the development of therapeutic interventions to support healthy aging. The Fifth Annual Midwest Aging Consortium Aging Research symposium, held from April 28 to 30, 2024, was hosted by The Ohio State University in Columbus, Ohio, and featured presentations from investigators across the Midwestern United States. This report summarizes the research presented at the symposium, whose topics included cellular senescence and the aging brain, metabolism and metabolic interventions, nutrition, redox mechanisms and biomarkers, and stress mechanisms. Abstract presentations and short talks highlighted early-stage and young investigators, whereas 2 keynote presentations anchored the symposium. Overall, this symposium showed the robustness of aging research in the Midwest and underscored the advantages of a collaborative approach to geroscience research., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Autophagy is a conserved mechanism that degrades damaged or superfluous cellular contents and enables nutrient recycling under starvation conditions. Many neurodegeneration-associated proteins are autophagy substrates, and autophagy upregulation ameliorates disease in many animal models of neurodegeneration by enhancing the clearance of toxic proteins, proinflammatory molecules, and dysfunctional organelles. Autophagy inhibition also induces neuronal and glial senescence, a phenomenon that occurs with increasing age in non-diseased brains as well as in response to neurodegeneration-associated stresses. However, aging and many neurodegeneration-associated proteins and mutations impair autophagy. This creates a potentially detrimental feedback loop whereby the accumulation of these disease-associated proteins impairs their autophagic clearance, facilitating their further accumulation and aggregation. Thus, understanding how autophagy interacts with aging, senescence, and neurodegenerative diseases in a temporal, cellular, and genetic context is important for the future clinical application of autophagy-modulating therapies in aging and neurodegeneration., Competing Interests: Declaration of interests D.C.R. is a consultant for Aladdin Healthcare Technologies Ltd., Mindrank AI, Nido Biosciences, Drishti Discoveries, Retro Biosciences, PAQ Therapeutics, and Alexion Pharma International Operations Limited. V.I.K. is a consultant for Longaevus Technologies., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aging is a critical biological process, with particularly notable impacts on the kidneys. Exosomes derived from human umbilical cord mesenchymal stem cells (hUC-MSCs) are capable of transferring various bioactive molecules, which exhibit beneficial therapeutic effects on kidney diseases. This study demonstrates that exosomes derived from hUC-MSCs ameliorate cellular senescence in the kidneys of naturally aging mice. These exosomes reduce the protein expression of senescence markers and senescence-associated secretory phenotypes (SASP) leading to fewer DNA damage foci and increased expression of the proliferation indicator Ki67. During the aging process, many proteins undergo phosphorylation modifications. We utilized data-independent acquisition (DIA) phosphoproteomics to study kidneys of naturally aging mice and those treated with hUC-MSC-derived exosomes. We observed elevated phosphorylation levels of the differentially phosphorylated proteins, Lamin A/C, at Ser390 and Ser392 sites, which were subsequently verified by western blotting. Overall, this study provides a new molecular characterization of hUC-MSC-derived exosomes in mitigating cellular senescence in the kidneys. SIGNIFICANCE: DIA phosphoproteomics was employed to investigate phosphorylated proteins in the kidney tissues of naturally aging mice with hUCMSC-exos treated. The results demonstrated that the DIA technique detected a higher abundance of phosphorylated proteins. We identified 24 significantly differentially phosphorylated proteins, and found that the phosphorylation of specific Lamin A/C sites is crucial for preventing cellular senescence. This study will help to better reveal the related phosphorylated proteins involved in hUCMSC-exos intervention in the kidneys of naturally aging mice, providing a foundation for future research on specific phosphorylation sites of proteins as potential therapeutic targets for renal aging-related diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The hypothalamus, in addition to controlling the main body's vital functions, is also involved in aging regulation. The aging process in the hypothalamus is accompanied by disturbed intracellular pathways, including Ca 2+ signaling and neuronal excitability in the brain. Intrinsic electrophysiological properties of individual neurons and synaptic transmission between cells is disrupted in the central nervous system of old animals. However, changes in neuronal excitability and excitation/inhibition balance with aging are specific to the type of neurons, brain region, and species. Glia-neuron interactions play a significant role in the brain and undergo remodeling accompanied by advanced loss of function with aging. In the current review, I have summarized the current understanding of the changes in the brain and especially in the hypothalamus with aging., (Copyright © 2025. Published by Elsevier Inc.)

Senescence, a crucial yet paradoxical phenomenon in cellular biology, acts as a barrier against cancer progression while simultaneously promoting aging and age-related pathologies. This duality underlines the importance of precise monitoring of senescence response, especially with regard to the proposed use of drugs selectively removing senescent cells. In particular, little is known about the role of senescence in neurons and in neurodegenerative diseases. Our study investigates the senescence response in neuroblastoma SH-SY5Y cells and human neural progenitor ReNcell VM cells exposed to doxorubicin, a chemotherapeutic agent known to induce DNA damage and subsequent senescence. Through a comprehensive analysis employing the most robust senescence markers, we characterized the senescence-associated patterns in these neural cell lines including cellular morphological changes, SA-beta-gal, γH2A.X, p21Waf1/Cip1 and p16Ink4a. Our findings indicate that ReNcell VM cells exhibit greater senescence-associated response at lower doxorubicin concentrations compared to SH-SY5Y cells. Additionally, we observed cell-type-specific differences in timing and levels of the expression of key cell cycle regulators during senescence. Our results emphasize the necessity of cell-type-specific strategies in senescence research with regard to implications as well as limitations for translation into aging and neurodegenerative disorders.

Mitophagy, the selective autophagic clearance of damaged mitochondria, is considered vital for maintaining mitochondrial quality and cellular homeostasis; however, its molecular mechanisms, particularly under basal conditions, and its role in cellular physiology remain poorly characterized. We recently demonstrated that basal mitophagy is a key feature of primary human cells and is downregulated by immortalization, suggesting its dependence on the primary cell state. Mechanistically, we demonstrated that the PINK1-PRKN-SQSTM1 pathway regulates basal mitophagy, with SQSTM1 sensing superoxide-enriched mitochondria through its redox-sensitive cysteine residues, which mediate SQSTM1 oligomerization and mitophagy activation. We developed STOCK1N-57534, a small molecule that targets and promotes this SQSTM1 activation mechanism. Treatment with STOCK1N-57534 reactivates mitophagy downregulated in senescent and naturally aged donor-derived primary cells, improving cellular senescence(-like) phenotypes. Our findings highlight that basal mitophagy is protective against cellular senescence and aging, positioning its pharmacological reactivation as a promising anti-aging strategy. Abbreviation: IR: ionizing radiation; ROS: reactive oxygen species; SARs: selective autophagy receptors.

Psychosocial stress and adversity have been linked to accelerated aging and increased risk for age-related diseases. Animal and in vitro studies have shown that exposure to stress hormones (catecholamines, glucocorticoids) can impact biological aging processes such as DNA damage and cellular senescence, suggesting they play a key role in links between stress and aging; however, these associations have not been well investigated in humans. We examined cross-sectional associations between chronic stress exposures, stress hormones, and biological aging markers in midlife adults and whether stress hormones mediated associations between stress and aging. Participants were 531 adults aged 26-78 years (M age  = 53.9, 50.1% female) in the nationally representative Midlife in the United States Refresher cohort. They reported chronic stress exposures in childhood and adulthood (Stressful Life Event Inventory) and provided 12-hour urine samples used to assess norepinephrine, epinephrine, and cortisol. RNA sequencing of peripheral blood mononuclear cells derived aging biomarkers: the DNA damage response (DDR; 30-gene composite), cellular senescence signal p16 INK4a (CDKN2A), and the pro-inflammatory senescence-associated secretory phenotype (SASP; 57-gene composite). Regression models adjusting for age, sex, race/ethnicity, BMI, smoking status, alcohol use, and medications revealed that more childhood exposures were associated with higher norepinephrine (β = 0.09, p = 0.04), independent from adult exposures. Higher norepinephrine was associated with elevated DDR expression (β = 0.17, p < 0.001). Higher norepinephrine (β = 0.14, p = 0.003) and epinephrine (β = 0.10, p = 0.02) were both associated with elevated SASP expression. Statistical mediation analyses implicated elevated norepinephrine as a plausible mediator of associations between childhood exposures and both DDR (unstandardized b = 0.005, 95% CI [0.0002, 0.011]) and SASP (b = 0.002, 95% CI [0.0001, 0.05]). Findings provide preliminary evidence in humans that stress hormones may impact key biological aging processes and may be a mechanism linking chronic stress exposures in childhood to accelerated aging later in life., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose of Review: Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by diffuse organ fibrosis and vasculopathy. Aberrant aging has been increasingly implicated in fibrotic diseases of the lung and other organs. The aim of this review is to summarize the established mechanisms of aging and how they may contribute to the pathogenesis of SSc., Recent Findings: Shortened telomeres are present in SSc patients with interstitial lung disease (SSc-ILD) and associate with disease severity and mortality. Although the cause of telomere length shortening is unknown, immune mechanisms may be at play. Senescent cells accumulate in affected organs of SSc patients and contribute to a pathologic cellular phenotype that can be profibrotic and inflammatory. In addition to identifying patients with a more severe phenotype, biomarkers of aging may help identify patients who have worse outcomes with immunosuppression., Summary: Aging mechanisms, including telomere dysfunction and cellular senescence, likely contribute to the progressive fibrosis, vasculopathy, and immune dysfunction of SSc. Further work is needed to understand whether aberrant aging is an initiator or perpetuator of disease, and whether this is cell or organ specific. A better understanding of the role aging mechanisms play in SSc will contribute to our understanding of the underlying pathobiology and may also influence management of patients exhibiting the aging phenotype., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Aging is a complex biological process that involves the gradual decline of cellular, tissue, and organ functions. In kidney, aging manifests as tubular atrophy, glomerulosclerosis, and progressive renal function decline. The critical role of senescence-associated macrophage in diseases, particularly kidney diseases, is increasingly recognized. During this process, macrophages exhibit a range of pro-damage response to senescent tissues and cells, while the aging of macrophages themselves also significantly influences disease progression, creating a bidirectional regulatory role between aging and macrophages. To explore this bidirectional mechanism, this review will elucidate the origin, characteristic, phenotype, and function of macrophages in response to the senescence-associated secretory phenotype (SASP), extracellular vesicles from senescent cells, and the senescence cell-engulfment suppression (SCES), particularly in the context of kidney disease. Additionally, it will discuss the characteristics of senescent macrophage, such as common markers, and changes in autophagy, metabolism, gene regulation, phagocytosis, antigen presentation, and exosome secretion, along with their physiological and pathological impacts on renal tissue cells. Furthermore, exploring therapies and drugs that modulate the function of senescent macrophages or eliminate senescent cells may help slow the progression of kidney aging and damage., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Purpose of Review: Giant cell arteritis (GCA) is an age-related autoimmune disease with a complex pathogenesis that involves several pathogenic mechanisms. This review provides recent critical insights into novel aspects of GCA pathogenesis., Recent Findings: The use of novel approaches, including multiomic techniques, has uncovered notable findings that broaden the understanding of GCA pathogenesis. TCF1hiCD4+ T cells have been identified as stem-like T cells residing in tertiary lymphoid structures in the adventitia of GCA aortic tissues, which likely supply the pathogenic effector T cells present in vasculitic lesions. Studies have demonstrated that fibroblasts present in GCA-inflamed arteries are not innocent bystanders, but they contribute to arterial inflammation via maintenance of Th1 and Th17 polarisation, cytokine secretion (IL-6, IL-1B, IL-12, and IL-23) and antigen presentation. Additionally, deregulated cellular senescence programs are present in GCA as an accumulation of IL-6 and matrix metalloproteinase 9-producing senescent cells have been identified in vasculitic lesions., Summary: Recent studies have unravelled interesting findings with potentially significant clinical relevance. Stem-like T cells are likely key contributors to vascular disease persistence, and targeted depletion or modulation of these cells holds promise in GCA management. Fibroblast-targeting therapies and senotherapeutics are also exciting prospects in the treatment of GCA., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Increased prevalence of skin ageing is a growing concern due to an ageing global population and has both sociological and psychological implications. The use of more clinically predictive in vitro methods for dermatological research is becoming commonplace due to initiatives and the cost of clinical testing. In this study, we utilise a well-defined and characterised bioengineered skin construct as a tool to investigate the cellular and molecular dynamics involved in skin ageing from a dermal perspective. Through incorporation of ageing fibroblasts into the dermal compartment we demonstrate the significant impact of dermal-epidermal crosstalk on the overlying epidermal epithelium. We characterise the paracrine nature of dermal-epidermal communication and the impact this has during skin ageing. Soluble factors, such as inflammatory cytokines released as a consequence of senescence associated secretory phenotype (SASP) from ageing fibroblasts, are known to play a pivotal role in skin ageing. Here, we demonstrate their effect on epidermal morphology and thickness, but not keratinocyte differentiation or tissue structure. Through a novel in vitro strategy utilising bioengineered tissue constructs, this study offers a unique reductionist approach to study epidermal and dermal compartments in isolation and tandem., (© 2025 The Author(s). Journal of Cellular Physiology published by Wiley Periodicals LLC.)

Aging is associated with a progressive decline in cellular function. To reset the aged cellular phenotype, various reprogramming approaches, including mechanical routes, have been explored. However, the epigenetic mechanisms underlying cellular rejuvenation are poorly understood. Here, we studied the cytoskeletal, genome-wide chromatin and transcriptional changes in young, aged, and mechanically rejuvenated fibroblasts using immunofluorescence, RNA sequencing, and Hi-C experiments. The mechanically rejuvenated aged fibroblasts, that had partially reset their transcription to a younger cell state, showed a local reorganization of the interchromosomal contacts and lamina-associated domains. Interestingly, the observed chromatin reorganization correlated with the transcriptional changes. Immunofluorescence experiments in the rejuvenated state confirmed increased actomyosin contractility like younger fibroblasts. In addition, the rejuvenated contractile properties were maintained over multiple cell passages. Overall, our results give an overview of how changes in the cytoskeleton, chromatin, and gene activity are connected to aging and rejuvenation.

Aging is the most common risk factor for Multiple Sclerosis (MS) disease progression. Cellular senescence, the irreversible state of cell cycle arrest, is the main driver of aging and has been found to accumulate prematurely in neurodegenerative diseases, including Alzheimer's and Parkinson's disease. Cellular senescence in the central nervous system of MS patients has recently gained attention, with several studies providing evidence that demyelination induces cellular senescence, with common hallmarks of p16INK4A and p21 expression, oxidative stress, and senescence-associated secreted factors. Here we discuss the current evidence of cellular senescence in animal models of MS and different glial populations in the central nervous system, highlighting the major gaps in the field that still remain. As premature senescence in MS may exacerbate demyelination and inflammation, resulting in inhibition of myelin repair, it is critical to increase understanding of cellular senescence in vivo, the functional effects of senescence on glial cells, and the impact of removing senescent cells on remyelination and MS. This emerging field holds promise for opening new avenues of treatment for MS patients., (© 2025 The Author(s). Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

In cells, the term "cellular aging" represents a collection of biological changes that can precede the proliferative senescence states. Cells more resistant to proliferative senescence, such as the ones found in the basal layer of the epidermis, may also exhibit these aging patterns. Therefore, cellular aging events could be induced by endogenous signals named here as cellular aging triggers (CATs) components. The superoxide anion (O 2 ⁻) could be a prime candidate for a CATs, as it is continuously produced by eukaryotic cells. To test this hypothesis, mitochondrial and cytoplasmic O 2 ⁻ imbalances were induced in HaCaT keratinocytes using rotenone (ROT, 30 µM), which inhibits mitochondrial complex I and paraquat (PQT, 30 µM), which increases O 2 ⁻ levels via redox cycling. ROT and PQT reduced cellular proliferation rate and elevated β-Galactosidase and transforming growth factor beta (TGF-β) levels. Furthermore, they increased the frequency of larger cells with nuclear alterations, the levels of oxidative markers, and interleukin 1β, a marker of the Senescence-Associated Secretory Phenotype (SASP). However, the mitochondrial O 2 ⁻ imbalance caused by ROT led to more pronounced alterations compared to PQT. These findings support the hypothesis that the existence of CAT components, such as the O2⁻ anion, plays a significant role in cellular aging., Competing Interests: Declarations. Conflict of interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Chronic kidney diseases (CKD) are a group of multi-factorial disorders that markedly impair kidney functions with progressive renal deterioration. Aging contributes to age-specific phenotypes in kidneys, which undergo several structural and functional alterations, such as a decline in regenerative capacity and increased fibrosis, inflammation, and tubular atrophy, all predisposing them to disease and increasing their susceptibility to injury while impeding their recovery. A central feature of these age-related processes is the activation of the p53/p21 pathway signaling. The pathway is a key player in cellular senescence, apoptosis, and cell cycle regulation, which are all key to maintaining the health of the kidney. P53 is a transcription factor and a tumor suppressor protein that responds to cell stress and damage. Persistent activation of cell p53 can lead to the expression of p21, an inhibitor of the cell cycle known as a cyclin-dependent kinase. This causes cells to cease dividing and leads to senescence, where cells can no longer increase. The accumulation of senescent cells in the aging kidney impairs kidney function by altering the microenvironment. As the number of senescent cells increases, the capacity of the kidney to recover from injury decreases, accelerating the progression of end-stage renal disease. This article review extensively explores the relationship between the p53/p21 pathway and cellular senescence within an aging kidney and the emerging therapeutic strategies that target it to overcome the impacts of cellular senescence on CKD., Competing Interests: Declarations Conflict of interest. Competing Interests: The author declares that there are no conflicts of interest., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Abstract: Cellular senescence, an irreversible state of cell cycle arrest characterized by phenotypic changes and a specific secretory profile, plays a dual role in liver health and disease. Under physiological conditions, senescence aids organ repair and regeneration, but its accumulation due to aging or pathological stress significantly contributes to chronic liver diseases, including alcoholic liver disease, metabolic dysfunction-associated steatohepatitis, liver fibrosis, and hepatocellular carcinoma. Senescence is identified by a range of cellular and molecular changes, such as morphological alterations, expression of cell cycle inhibitors, senescence-associated β-galactosidase activity, and nuclear membrane changes. The onset of senescence in organ cells can affect the entire organism, primarily through the senescence-associated secretory phenotype, which has autocrine, paracrine, and endocrine effects on tissue microenvironments. The objective of this review is to offer a contemporary overview of the pathophysiological events involving hepatic senescent cells and to elucidate their role in the onset and progression of liver diseases, particularly through mechanisms like telomere shortening, genomic and mitochondrial DNA damage, and inflammation. Additionally, this review discusses the emerging senolytic therapies aimed at targeting senescent cells to delay or mitigate liver disease progression. The therapeutic potential of these interventions, alongside their safety and effectiveness, highlights the need for further research to refine these approaches and address unresolved problems in the field of hepatic cellular senescence., (Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Cellular senescence is involved in the progression of neurodegenerative diseases. Motor neurons exhibit senescence-like alterations in ALS. BRD7, identified as a regulatory factor associated with cellular senescence, its function in ALS remains unclear. This study aims to investigate the potential role and mechanisms of BRD7 in ALS. We analyzed RNA levels using qRT-PCR, protein levels through immunofluorescence and western blot, and apoptosis via TUNEL staining. Cell transfection was conducted for in vitro experiments. The level of β-galactosidase was measured by β-galactosidase activity detection kit. ALS motor neurons exhibited senescence-like alterations, characterized by increased activity of p53, p21, and β-galactosidase, as well as reduced lamin B1 staining. Additionally, the expression of BRD7 was upregulated and induced cellular senescence and apoptosis. Downregulation of BRD7 alleviates the cellular senescence by inhibiting p21 rather than p53. Knockdown of BRD7 inhibited p53 mitochondrial translocation, leading to reduced apoptosis. Our results suggest that BRD7 plays an important role in the survival of ALS motor neurons. BRD7 knockdown can reduce cellular senescence and apoptosis by inhibiting p21 and p53 mitochondrial translocation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Traumatic brain injury (TBI) and stroke pose major health challenges, impacting millions of individuals globally. Once considered solely acute events, these neurological conditions are now recognized as enduring pathological processes with long-term consequences, including an increased susceptibility to neurodegeneration. However, effective strategies to counteract their devastating consequences are still lacking. Cellular senescence, marked by irreversible cell-cycle arrest, is emerging as a crucial factor in various neurodegenerative diseases. Recent research further reveals that cellular senescence may be a potential driver for secondary neurodegeneration following brain injury. Herein, we synthesize emerging evidence that TBI and stroke drive the accumulation of senescent cells in the brain. The rationale for targeting senescent cells as a therapeutic approach to combat neurodegeneration following TBI/stroke is outlined. From a translational perspective, we emphasize current knowledge and future directions of senolytic therapy for these neurological conditions., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: All authors have read and approved the final manuscript for publication. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Vascular aging, a common pathogenesis of senile chronic diseases, significantly increases morbidity and mortality in older adults; its intricate cellular and molecular mechanisms necessitate further investigation. Lumican (LUM) and integrin α2β1 are profibrotic extracellular matrix proteins and vital cell regulatory receptors, respectively. However, their roles in vascular aging remain unclear. This study sought to elucidate the connection between LUM and vascular aging as well as the biological mechanism of LUM/integrin α2β1 in this process. Using an enzyme-linked immunosorbent assay, we discovered that plasma LUM was elevated in vascular aging individuals and was positively correlated with brachial-ankle pulse wave velocity. Additionally, immunohistochemical and Western blot analyses confirmed LUM upregulation in arteries of older adults and aged mice, as well as in senescent vascular smooth cells (VSMCs). Wild-type and LUM semiknockout (Lum-/+) mice, along with primary VSMCs extracted from these mice, were exposed to angiotensin II to induce a stress-induced senescence model. LUM semiknockout mitigated angiotensin II-induced arteriosclerosis, hypertension, vascular aging, and remodeling in mice. Both in vitro and in vivo studies revealed that LUM deficiency suppressed p53, p21, collagen 1, and collagen 3 upregulation and synthetic phenotype formation in VSMCs stimulated by angiotensin II. Treating VSMCs with an integrin α2β1 antagonist reversed the aforementioned changes triggered by LUM proteins. Briefly, LUM functions as a potential marker and risk factor for vascular aging and promotes pathological changes by affecting integrin α2β1 in VSMCs. This study introduces a novel molecular target for the early diagnosis and treatment of vascular aging and age-related vascular diseases., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Gerontological Society of America.)

Age is an important risk factor of stroke, cognitive decline, and dementia. Senescent endothelial cells (ECs) accumulate with advancing age through exposure to cellular stress, such as that exerted by hypertension and diabetes. These senescent ECs have altered characteristics, such as altered tight junction proteins, use of a more indiscriminate transcellular transport system, increased inflammation, and increased immune cell interactions. ECs are the main component of the blood-brain barrier (BBB), separating the brain from systemic circulation. As senescent ECs accumulate in the BBB, their altered functioning results in the disruption of the barrier. They have inadequate barrier-forming properties, disrupted extracellular matrix, and increased transcytosis, resulting in an overly permeable barrier. This disruption of the BBB can have important effects in stroke and cognitive impairment, as presented in this review. Besides increasing the permeability of the BBB, senescent ECs can also impair angiogenesis and vascular remodeling, which in ischemic stroke may increase risk of hemorrhagic transformation and worsen outcomes. Senescent ECs may also contribute to microvascular dysfunction, with disruption of cerebral perfusion and autoregulation. These may contribute to vascular cognitive impairment along with increased permeability. With an aging population, there is growing interest in targeting senescence. Several ongoing trials have been evaluating whether senolytics can slow aging, improve vascular health, and reduce the risk of stroke and cognitive decline.

Low back pain caused by intervertebral disc degeneration (IDD) has emerged as a significant global public health concern, with far-reaching consequences for patients' quality of life and healthcare systems. Although previous research have revealed that the mechanisms of intervertebral disc cell apoptosis, pyroptosis and necroptosis can aggravate IDD damage by mediating inflammation and promoting extracellular matrix degradation, but they cannot explain the connection between different cell death mechanisms and ion metabolism disorders. The latest study shows that cell death mechanisms such as cellular senescence, ferroptosis, and cuproptosis, and PANopotosis have similar roles in the progression of intervertebral disc degeneration, but not exactly the same damage mechanism. This paper summarizes the effects of various cell death patterns on the disease progression of IDD, related molecular mechanisms and signaling pathways, providing new perspectives and potential clinical intervention strategies for the prevention and treatment of IDD., Competing Interests: Declarations. Ethical approval: Not applicable. Informed consent: Not applicable. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

In this study, we evaluate lipids and select proteins in human lung fibroblasts (hLFs) to interrogate changes occurring due to aging and senescence. To study single cell populations, a comparison of cells adhered onto slides using poly-d-lysine versus centrifugal force deposition was first analyzed to determine whether specific alterations were observed between preparations. The poly-d-lysine approach was then utilized to interrogate the lipidome of the cell populations and further evaluate potential applications of the MALDI-immunohistochemistry (IHC) platform for single-cell-level analyses. Two protein markers of senescence, vimentin and p21, were both observed within the fibroblast populations and quantified. Lipidomic analysis of the fibroblasts found 12 lipids significantly altered because of replicative senescence, including fatty acids, such as stearic acid, and ceramide phosphoethanolamine species (CerPE). Similar to previous reports, alterations were detected in putative fatty acid building blocks, ceramides, among other lipid species. Altogether, our results reveal the ability to detect lipids implicated in senescence and show alterations to protein expression between normal and senescent fibroblast populations, including differences between young and aged cells. This report is the first time that the MALDI-IHC system has been utilized at a single-cell level to analyze both protein expression and lipid profiles in cultured cells, with a particular focus on changes associated with aging and senescence.

Epithelial-Mesenchymal Transition (EMT) is a fundamental biological process involved in embryonic development, wound healing, and cancer progression. In lung cancer, EMT is a key regulator of invasion and metastasis, significantly contributing to the fatal progression of the disease. Age-related factors such as cellular senescence, chronic inflammation, and epigenetic alterations exacerbate EMT, accelerating lung cancer development in the elderly. This review describes the complex mechanism among EMT and age-related pathways, highlighting key regulators such as TGF-β, WNT/β-catenin, NOTCH, and Hedgehog signalling. We also discuss the mechanisms by which oxidative stress, mediated through pathways involving NRF2 and ROS, telomere attrition, regulated by telomerase activity and shelterin complex, and immune system dysregulation, driven by alterations in cytokine profiles and immune cell senescence, upregulate or downregulate EMT induction. Additionally, we highlighted pathways of transcription such as SNAIL, TWIST, ZEB, SIRT1, TP53, NF-κB, and miRNAs regulating these processes. Understanding these mechanisms, we highlight potential therapeutic interventions targeting these critical molecules and pathways., Competing Interests: Declaration of Competing Interest MKK received consultant honoraria from the CBRS, Noida. Rest of the author declares no financial interests., (Copyright © 2024. Published by Elsevier B.V.)

Adipose tissue (AT), the largest energy storage reservoir and endocrine organ, plays a crucial role in regulating systemic energy metabolism. As one of the most vulnerable tissues during aging, the plasticity of AT is impaired. With age, AT undergoes redistribution, characterized by expansion of visceral adipose tissue (VAT) and reduction of peripheral subcutaneous adipose tissue (SAT). Additionally, age-related changes in AT include reduced adipogenesis of white adipocytes, decreased proliferation and differentiation capacity of mesenchymal stromal/stem cells (MSCs), diminished thermogenic capacity in brown/beige adipocytes, and dysregulation of immune cells. Specific and sensitive hallmarks enable the monitoring and evaluation of the biological changes associated with aging. In this study, we have innovatively proposed seven characteristic hallmarks of AT senescence, including telomere attrition, epigenetic alterations, genomic instability, mitochondrial dysfunction, disabled macroautophagy, cellular senescence, and chronic inflammation, which are intricately interconnected and mutually regulated. Finally, we discussed anti-aging strategies targeting AT, offering insights into mitigating or delaying metabolic disturbances caused by AT senescence., Competing Interests: Declaration of Competing Interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ageing is accompanied by a persistent, low-level inflammation, termed "inflammageing", which contributes to the pathogenesis of age-related diseases. Mitochondria fulfil multiple roles in host immune responses, while mitochondrial dysfunction, a hallmark of ageing, has been shown to promote chronic inflammatory states by regulating the production of cytokines and chemokines. In this review, we aim to disentangle the molecular mechanisms underlying this process. We describe the role of mitochondrial signalling components such as mitochondrial DNA, mitochondrial RNA, N-formylated peptides, ROS, cardiolipin, cytochrome c, mitochondrial metabolites, potassium efflux and mitochondrial calcium in the age-related immune system activation. Furthermore, we discuss the effect of age-related decline in mitochondrial quality control mechanisms, including mitochondrial biogenesis, dynamics, mitophagy and UPR mt , in inflammatory states upon ageing. In addition, we focus on the dynamic relationship between mitochondrial dysfunction and cellular senescence and its role in regulating the secretion of pro-inflammatory molecules by senescent cells. Finally, we review the existing literature regarding mitochondrial dysfunction and inflammation in specific age-related pathological conditions, including neurodegenerative diseases (Alzheimer's and Parkinson's disease, and amyotrophic lateral sclerosis), osteoarthritis and sarcopenia., Competing Interests: Competing interests The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The current narrative review was planned to elucidate the interplay between acupuncture, a cornerstone of Traditional Chinese Medicine, and the modulation of cellular mechanisms via Forkhead box O transcription factors, focussing on autophagy and cellular senescence. Autophagy, essential for cellular health, and cellular senescence, associated with aging and age-related diseases, are both significantly influenced by Forkhead box O transcription factors among other regulatory factors and pathways. These factors, known to diminish with age, play a pivotal role in promoting longevity. The current review analysed experimental models demonstrating acupuncture's capacity to activate Forkhead box O transcription factors, thereby inducing autophagy and reducing cellular senescence. Evidence from studies on human fibroblasts, ageing animal models, obesity-induced insulin resistance, and osteoporosis corroborates the beneficial effects of acupuncture. Despite these promising findings, the complexities of Forkhead box O transcription factors' activation by acupuncture and their precise impact on cellular processes warrant further investigation with a particular focus on the distinct roles of Forkhead box O isoforms.

Oxidative stress and cell senescence are both important drivers of ageing and age-associated disease and disability. In vitro, they are closely interconnected in a chicken-and-egg relationship: Not only is oxidative stress an important cause of cell senescence, but senescent cells are also sources of oxidative stress, obscuring cause-effect relationships during the ageing process. We hypothesize that cell senescence is a significant cause of tissue and systemic oxidative stress during ageing. This review aims to critically summarize the available evidence for this hypothesis. After summarizing the cellular feedback mechanisms that make oxidative stress an integral part of the senescent phenotype, it critically reviews the existing evidence for a role of senescent cells as causes of oxidative stress during mammalian ageing in vivo, focussing on results from intervention experiments. It is concluded that while the available data are in agreement with this hypothesis, they are still too scarce to support a robust conclusion., Competing Interests: Declaration of Competing Interest The author declares no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Background & Aims: Biliary complications are a major cause of morbidity and mortality in liver transplantation. Up to 25% of patients that develop biliary complications require additional surgical procedures, re-transplantation or die in the absence of a suitable regraft. Here, we investigate the role of the primary cilium, a highly specialised sensory organelle, in biliary injury leading to post-transplant biliary complications., Methods: Human biopsies were used to study the structure and function of primary cilia in liver transplant recipients that develop biliary complications (n = 7) in comparison with recipients without biliary complications (n = 12). To study the biological effects of the primary cilia during transplantation, we generated murine models that recapitulate liver procurement and cold storage, and assessed the elimination of the primary cilia in biliary epithelial cells in the K19CreER T Kif3a fl /fl mouse model. To explore the molecular mechanisms responsible for the observed phenotypes we used in vitro models of ischemia, cellular senescence and primary cilia ablation. Finally, we used pharmacological and genetic approaches to target cellular senescence and the primary cilia, both in mouse models and discarded human donor livers., Results: Prolonged ischemic periods before transplantation result in ciliary shortening and cellular senescence, an irreversible cell cycle arrest that blocks regeneration. Our results indicate that primary cilia damage results in biliary injury and a loss of regenerative potential. Senescence negatively impacts primary cilia structure and triggers a negative feedback loop that further impairs regeneration. Finally, we explore how targeted interventions for cellular senescence and/or the stabilisation of the primary cilia improve biliary regeneration following ischemic injury., Conclusions: Primary cilia play an essential role in biliary regeneration and we demonstrate that senolytics and cilia-stabilising treatments provide a potential therapeutic opportunity to reduce the rate of biliary complications and improve clinical outcomes in liver transplantation., Impact and Implications: Up to 25% of liver transplants result in biliary complications, leading to additional surgery, retransplants, or death. We found that the incidence of biliary complications is increased by damage to the primary cilium, an antenna that protrudes from the cell and is key to regeneration. Here, we show that treatments that preserve the primary cilia during the transplant process provide a potential solution to reduce the rates of biliary complications., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: The superficial zone cells in articular cartilage (SFZCs) have been identified as stem/progenitor chondrocytes and promoted cell self-renewal in the osteoarthritis (OA). Several studies emphasized the involvement of senescence and autophagy in OA. Interleukin-1β (IL-1β) is one of the main inflammatory mediators of OA, and whether it induces senescence and autophagy in SFZCs remains unclear. The present study aimed to investigate autophagy flux, mitochondrial function, and intracellular reactive oxygen species (ROS) that resulted in senescence in SFZCs induced by IL-1β., Methods: Using western blotting, reverse transcription-quantitative PCR, immunofluorescence, intracellular ROS detection, mitochondrial staining, and determination of mitochondrial membrane potential, we tested senescence and autophagy markers in SFZCs induced by IL-1β in vitro . The consequences of mitochondrial function and ROS were also studied with IL-1β-induced senescence., Results: IL-1β treatment decreased SFZC proliferation, induced SFZC senescence, and reduced SFZCs' chondrogenic differentiation capacity. Moreover, IL-1β impaired autophagy flux, and the autophagy activator, rapamycin, attenuated the senescence of SFZCs. IL-1β-induced autophagy defect resulted in mitochondrial dysfunction and overproduction of ROS, and autophagy activation notably protected against mitochondrial dysfunction and reduced the levels of ROS. Moreover, antioxidant N-acetylcysteine reversed the senescence of IL-1β in SFZCs., Conclusion: IL-1β promotes autophagy impairment and subsequently results in dysfunctional mitochondria and overproduction of ROS, which finally causes SFZC senescence., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.