bims-cesemi 2025-12-28 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2025–12–28
eleven papers selected by
Julio Cesar Cardenas, Universidad Mayor

Senescent Mesenchymal Stromal Cells Differentially Alter Adipogenesis in Adipose Tissue, Skeletal Muscle, and Bone Marrow.
Senescent Cell Clearance Ameliorates Temporal Lobe Epilepsy and Associated Spatial Memory Deficits in Mice.
Senolytic elimination of therapy-induced senescent cells by ABT-263 improves chemotherapeutic efficacy in esophageal squamous cell carcinoma.
Navitoclax acts synergistically with irradiation to induce apoptosis in preclinical models of H3K27M-altered diffuse midline glioma.
Preliminary Evidence for Increased Histone Succinylation as a Potential Epigenetic Marker for Longevity.
VDAC1: at the crossroads of cancer signalling and metabolism.
Pterostilbene mitigates the senescence of human dermal fibroblast cells by enhancing mitochondrial quality.
Cellular senescence in age-related musculoskeletal diseases: intercellular communication as a driver of disease pathogenesis.
Exercise-induced β-hydroxybutyrate contributes to cognitive improvement in aging mice.
Mitochondrial polarization and redox homeostasis couple glycolysis-to-OXPHOS metabolic rewiring to lifespan extension in C. elegans.
β-Hydroxy-β-Methylbutyrate enhances fast-twitch muscle and mitochondrial function, histopathology, and mTORC1 signalling in the mdx dystrophic mouse.

Obesity (Silver Spring). 2025 Dec 24.

Senescent Mesenchymal Stromal Cells Differentially Alter Adipogenesis in Adipose Tissue, Skeletal Muscle, and Bone Marrow.

Xu Zhang, Madison L Doolittle, Ting Fan, Utkarsh Tripathi, Yan Er Ng, Xinyi Jiang, João F Passos, Diana Jurk, David G Monroe, Tamara Tchkonia, James L Kirkland, Paul D Robbins, Sundeep Khosla, Nathan K LeBrasseur.

   OBJECTIVE: Aging alters mesenchymal stromal cell (MSC) function, leading to dysregulated adipogenesis across tissues through biased lineage commitment. Fat redistribution from adipose depots to skeletal muscle and bone marrow is common in aging, but the underlying mechanisms remain unclear. This study investigates how MSC senescence modulates adipogenesis.
METHODS: Primary MSCs were isolated from mouse skeletal muscle (FAPs), adipose tissue (APCs), and bone marrow (BMSCs). Single-cell RNA sequencing was performed to compare transcriptional profiles among these populations. In vitro adipogenic differentiation and DNA damage-induced senescence assays were conducted, and the effects of autologous conditioned media from senescent MSCs on adipogenesis were assessed.
RESULTS: Transcriptional analyses revealed that FAPs and APCs share greater similarity with each other than with BMSCs. All MSC types exhibited adipogenic potential and developed a robust senescence-associated secretory phenotype (SASP) upon senescence induction. Conditioned media from senescent MSCs enhanced adipogenesis in BMSCs but inhibited adipogenesis in FAPs and APCs, revealing tissue-specific paracrine effects.
CONCLUSIONS: MSC senescence reprograms adipogenic bias in a tissue-dependent, non-cell autonomous manner, contributing to age-related fat redistribution among adipose tissue, skeletal muscle, and bone marrow. Understanding these mechanisms may provide new therapeutic approaches for improving tissue composition and function in the context of aging.

Keywords:  adipogenesis; mesenchymal stromal cells; senescence; senescence‐associated secretory phenotype

DOI:  https://doi.org/10.1002/oby.70119
Ann Neurol. 2025 Dec 22.

Senescent Cell Clearance Ameliorates Temporal Lobe Epilepsy and Associated Spatial Memory Deficits in Mice.

Tahiyana Khan, David J McFall, Abbas I Hussain, Logan A Frayser, Timothy P Casilli, Meaghan C Steck, Irene Sanchez-Brualla, Noah M Kuehn, Michelle Cho, Jacqueline A Barnes, Brent T Harris, Stefano Vicini, Patrick A Forcelli.

OBJECTIVE: The pharmacological treatment of temporal lobe epilepsy (TLE), a disorder characterized by recurrent seizures and cognitive dysfunction, is limited to symptomatic control. Identifying novel targets to modify disease progression is of great clinical and translational interest. Cellular senescence has been recently implicated in the development and progression of other neurodegenerative diseases, but its role in TLE is unstudied.
METHODS: We first investigated cellular senescence markers in resected hippocampi from patients with medically intractable TLE through multiplexed immunofluorescence. We next used a mouse model of TLE (pilocarpine induced status epilepticus [SE]) for a combination of immunohistochemistry, behavioral testing, and electroencephalogram (EEG) monitoring. We implemented 2 strategies for removal of senescent cells (SCs), a genetic mouse model allowing for targeted senolysis, and a pharmacological approach using dasatinib and quercetin.
RESULTS: We found a 5-fold elevation of senescent glia in human TLE cases as compared with controls. In mice, we found increases in senescence markers at both the transcript and protein level and predominantly expressed in microglia, which developed within 2 weeks following SE. Senolytic treatment produced a 50% reduction in SCs, rescued long-term potentiation deficits, normalized spatial memory impairments, reduced seizures, and protected a third of animals from epilepsy.
INTERPRETATION: Our data demonstrate that SCs accumulate in both human TLE and in a mouse model of TLE and suggest that clearing SCs may be a viable strategy to reduce seizures and associated cognitive comorbidities. ANN NEUROL 2025.

DOI: https://doi.org/10.1002/ana.78118
Biochem Pharmacol. 2025 Dec 19. pii: S0006-2952(25)00924-4. [Epub ahead of print]245 117659

Senolytic elimination of therapy-induced senescent cells by ABT-263 improves chemotherapeutic efficacy in esophageal squamous cell carcinoma.

Dan Zhang, Ju Zhu, Rui Zou, Han Zhang, Bao-Ping Yu, Pan Li, Yang Luo, Zheng Jiang, Yu Hou, Jian-Wei Zhang.

  Esophageal squamous cell carcinoma (ESCC) is routinely treated with platinum-based chemotherapy but almost inevitably relapses. Our previous study demonstrated that cisplatin (CDDP) induced ESCC cell senescence, and senescent cells promoted the aggressive behaviors of neighboring cancer cells through the senescence-associated secretory phenotype (SASP). Notably, the use of 'senolytic' drugs that selectively remove senescent cells by inducing apoptosis has been proven to improve therapeutic efficacy, but their potential application in ESCC therapy has not yet been studied. In this study, we observed that therapy-induced ESCC cell senescence was associated with poor prognosis of ESCC patients. We found that anti-apoptotic BCL-2 family member BCL-XL mediated the survival of CDDP-induced senescent ESCC cells, and senolytic drug ABT-263 (navitoclax, an inhibitor of BCL-2 and BCL-XL) selectively eliminated senescent cells by triggering apoptosis, thereby attenuating SASP-driven ESCC cell proliferation and migration in vitro and improving CDDP efficacy in a mouse model of ESCC. Mechanistically, the enhanced interaction between BCL-XL and pro-apoptotic effector protein BAX conferred apoptosis resistance in senescent ESCC cells, and ABT-263 treatment disrupted this interaction to activate apoptosis. Overall, our data indicate that CDDP-induced senescent ESCC cells could be eliminated using senolytic drugs that target BCL-XL, and thus senolytic therapy could be a potential effective strategy for improving chemotherapeutic efficacy in ESCC.

Keywords:  ABT-263; Cellular senescence; Cisplatin; Esophageal squamous cell carcinoma; Senolytic

DOI:  https://doi.org/10.1016/j.bcp.2025.117659
Sci Rep. 2025 Dec 22.

Navitoclax acts synergistically with irradiation to induce apoptosis in preclinical models of H3K27M-altered diffuse midline glioma.

Ashley Vardon, Scott Haston, Hiba Hamdi, Grace Cooksley, Romain Guiho, Diana Carvalho, Rebecca Carter, Jessica Katherine Rowena Boult, Daniel Gharai, Ielyaas Cloete, James Grey, John Apps, Daohong Zhou, Guangrong Zheng, Ramón Martínez-Máñez, Mark Francis Lythgoe, Laura Kate Donovan, Angel Montero Carcaboso, Owen Williams, Ying Hong, Paula Alexandre, Jesus Gil, Jamie Adam Dean, David Michod, Chris Jones, Darren Hargrave, Juan-Pedro Martinez-Barbera.

  Diffuse midline gliomas (DMGs) with histone H3K27M mutations represent a devastating paediatric brain cancer characterised by abysmal prognosis and limited treatment options. The only approved treatment is radiotherapy (RT), but most of the tumours relapse with fatal consequences. The effects of RT remain unknown because patients are not biopsied during treatment. Here, we sought to investigate whether irradiation leads to senescence induction in DMG and explore the efficacy of senolytics. We show that ionising radiation induces senescence in various H3K27M-altered DMG cell lines. Senescence induction is demonstrated by immunocytochemistry, RNA-sequencing and analysis of SASP factors by ELISA. Through testing several senolytic compounds, we identify that Bcl2 family inhibitors (e.g., Navitoclax) act as potent senolytics, driving senescent DMG cells into apoptosis, primarily via Bcl-xL inhibition. Reinforcing these findings, proteolysis-targeting chimeras (PROTACs) targeting Bcl-xL and galacto-conjugated Navitoclax (Nav-Gal) also exhibit strong senolytic activity against senescent DMG cancer cells. Finally, we show that a combination of irradiation with Navitoclax enhances cancer cell apoptosis in an orthotopic xenograft DMG model. Together, the data demonstrate that ionising irradiation leads to senescence induction in H3K27M-altered human DMG cell lines, making them particularly sensitive to apoptosis through Bcl-xL inhibition.

Keywords:  BH3-mimetics; Bcl-xL; Cellular senescence; H327M-altered diffuse midline glioma; Senolytic therapy

DOI:  https://doi.org/10.1038/s41598-025-32676-6
Aging Cell. 2026 Jan;25(1): e70346

Preliminary Evidence for Increased Histone Succinylation as a Potential Epigenetic Marker for Longevity.

Stephanie Stransky, Sarah Graff, Kai Mao, Derek M Huffman, Sofiya Milman, Nir Barzilai, Simone Sidoli.

  Histone post-translational modifications (PTMs) are critical regulators of chromatin structure and gene expression, with broad implications for development, metabolism, and aging. While canonical modifications such as methylation and acetylation are well characterized, the role of histone succinylation remains poorly understood. Here, we investigated histone succinylation in the context of aging and exceptional longevity. Using mass spectrometry-based proteomics, we quantified histone succinylation in B-cells from four groups: young individuals, older individuals without parental longevity (OPUS), long-lived individuals, and offspring of long-lived individuals (OPEL). We found that histone succinylation was significantly elevated in the OPEL group compared to both young and OPUS cohorts. Nuclear proteomics further revealed enrichment of succinylated proteins in OPEL samples, supporting a role for succinylation in chromatin organization. To test whether succinate availability impacts healthspan, we supplemented middle-aged mice with succinic acid. While body weight, frailty index, and cognition were unaffected, succinic acid improved motor coordination and muscle strength. Together, our findings provide preliminary evidence that enhanced histone succinylation may serve as a protective epigenetic mechanism in individuals predisposed to exceptional longevity, and that succinate supplementation can selectively improve aspects of physical performance during aging.

Keywords:  aging; chromatin modifications; epigenetics; healthspan; histone succinylation; longevity; progeny of long‐lived individuals

DOI:  https://doi.org/10.1111/acel.70346
Expert Rev Proteomics. 2025 Dec 26. 1-17

VDAC1: at the crossroads of cancer signalling and metabolism.

Mahima Choudhari, Khushman Taunk, Bhargab Kalita, Srikanth Rapole.

   INTRODUCTION: Mitochondrial membrane proteins are key regulators of mitochondrial physiology and function. Voltage-dependent anion channel 1 (VDAC1), also termed mitochondrial porin, regulates metabolite and ion exchange across the outer mitochondrial membrane. It governs mitochondrial bioenergetics, apoptotic signaling, redox balance, and intracellular calcium homeostasis. VDAC1's function is shaped by its structure, expression, post-translational modifications, and interactions with other proteins, and is regulated by major signaling pathways including AMPK, PI3K/Akt, and mTOR. Furthermore, VDAC1 has not been extensively explored for its involvement in the crosstalk between cellular signalling and metabolism.
AREAS COVERED: This review highlights the central role of VDAC1 in cancer progression, emphasizing its involvement in both metabolic reprogramming, a hallmark of cancer, and the modulation of key cellular signaling pathways. We summarize the multifaceted functions of VDAC1 in orchestrating metabolic flux and regulating oncogenic signaling networks.
EXPERT OPINION: Metabolism and signal transduction are interconnected, but this crosstalk is not well explored. In recent years, the clinical significance of voltage-dependent anion channels in human health and disease has become more evident. It is worth exploring the role of VDAC1 as a metabolic and signaling pathway regulator. Studying this interconnection can give us a better understanding of cancer.

Keywords:  Calcium homeostasis; VDAC1; cancer signaling; metabolism; omics; post-translational modifications; therapeutics

DOI:  https://doi.org/10.1080/14789450.2025.2607512
Front Pharmacol. 2025 ;16 1732154

Pterostilbene mitigates the senescence of human dermal fibroblast cells by enhancing mitochondrial quality.

Xinyu Zhou, Ning Wang, Jihua Wei, Guizhi Li, Zhengwei Lue, Chang Liu, Qi Bao, Zhe Feng, Minjie Zhang, Hu Huang, Yue Li, Jing Wang, Xiangnan Zhang.

   Introduction: Pterostilbene (PT), a natural polyphenol found in blueberries and several grape varieties, exhibits pleotropic pharmacological effects. PT reduced the makers of aging caused by either ultraviolet (UV) light exposure or chemical stress in keratinocytes, whereas its potential anti-aging effects and underlying mechanisms in the dermis have not been elucidated.
Methods: The anti-senescence effects of PT were investigated in human dermal fibroblasts (HDFs) using models of UVB-induced acute oxidative stress and replicative senescence. Key assays included senescence-associated beta-galactosidase (SA-β-gal) activity, RT-PCR, western blotting, immunofluorescence, live-cell confocal imaging with fluorescent probes, flow cytometry and mitochondrial respiration analysis. A mouse model of UVB-induced skin damage was used to evaluate PT's anti-aging effects in vivo through histopathological examination and western blot analysis.
Results: PT treatment mitigated senescence in HDFs, as shown by reduced SA-β-gal activity, p16, and p21, along with increased collagen expression. It restored mitochondrial morphology, MMP, and reduced mitochondrial reactive oxygen species in both senescent models. Furthermore, PT improved mitochondrial basal respiration, ATP production, and maximal respiration. Mechanistically, PT promoted mitophagy, indicated by enhanced TOM20/LC3 colocalization. In vivo, topical PT restored collagen, dermal thickness, and LC3, while reducing p21 levels in UVB-exposed mice.
Discussion: Our findings demonstrate that PT delays dermal senescence by enhancing mitochondrial quality via enhancing mitophagy. These results highlight PT as a promising anti-aging agent capable of countering both intrinsic and extrinsic aging in the dermis.

Keywords:  human dermal fibroblasts cells (HDFs); mitochondria; mitophagy; pterostilbene; senescent; skin aging

DOI:  https://doi.org/10.3389/fphar.2025.1732154
Front Med. 2025 Dec 27.

Cellular senescence in age-related musculoskeletal diseases: intercellular communication as a driver of disease pathogenesis.

Ilya Klabukov, Elizabeth Skornyakova, Daria Eygel, Denis Baranovskii, Peter Shegay, Andrey Kaprin.

DOI: https://doi.org/10.1007/s11684-025-1177-8
J Sport Health Sci. 2025 Dec 18. pii: S2095-2546(25)00121-8. [Epub ahead of print] 101113

Exercise-induced β-hydroxybutyrate contributes to cognitive improvement in aging mice.

Lian Wang, Liwei Mao, Danlin Zhu, Ke Li, Haoyang Gao, Muge Zhou, Jiabin Wu, Dan Yang, Ze Wang, Wenhong Wang, Yifan Guo, Yingying Xu, Peijie Chen, Weihua Xiao.

   BACKGROUND: Aging is a major contributor to cognitive decline and neurodegeneration, yet effective interventions to counteract aging-related neuronal dysfunction remain limited. β-hydroxybutyrate (β-HB), a ketone body elevated during fasting or aerobic exercise, functions as both an energy substrate and a signaling metabolite.
METHODS: We assessed the effects of exercise-induced and exogenously supplemented β-HB on cognitive performance in aging mice. To examine the role of endogenous β-HB metabolism, we used 3-hydroxybutyrate dehydrogenase 1 (BDH1) knockout mice. In vitro, we investigated the impact of G protein-coupled receptor 109A (GPR109A) knockdown on β-HB-mediated activation of peroxisome proliferator-activated receptor gamma (PPARγ) and downstream pathways.
RESULTS: Exercise elevated circulating β-HB levels and improved cognitive outcomes in aging mice. Exogenous β-HB supplementation mimicked these benefits. Loss of BDH1 impaired endogenous β-HB production and attenuated both exercise- and β-HB-induced cognitive improvements. In vitro, GPR109A knockdown suppressed β-HB-driven activation of PPARγ and downstream neuroprotective pathways linked to inflammation and oxidative stress.
CONCLUSION: These findings identify the β-HB/GPR109A-PPARγ axis as a key mediator of exercise-induced cognitive enhancement in aging. β-HB emerges as a potential therapeutic candidate to mitigate brain aging and cognitive decline.

Keywords:  BDH1; Exercise; GPR109A; PPARγ; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.jshs.2025.101113
MicroPubl Biol. 2025 ;2025

Mitochondrial polarization and redox homeostasis couple glycolysis-to-OXPHOS metabolic rewiring to lifespan extension in C. elegans.

Anwaar Ali, Shanmuganathan Balakrishnan, Jiayu Xiang, Haesoo Bae, Minou Tsujishita, Amina Abulimiti, Bence Nemeth, Michalis Barkoulas, Kambiz N Alavian.

Mitochondria are essential for maintaining cellular homeostasis throughout life. Here, we investigated the differential effects of glucose and galactose, as well as glycolytic inhibition, on C. elegans lifespan in relation to mitochondrial membrane potential and reactive oxygen species (ROS) levels. Our results show that long-term treatment with glucose reduces both lifespan and mitochondrial membrane potential, whereas galactose increases them. The increase in mitochondrial membrane potential and lifespan is inversely correlated with mitochondrial ROS levels, suggesting a role for mitohormesis in lifespan extension.

DOI: https://doi.org/10.17912/micropub.biology.001858
Am J Physiol Cell Physiol. 2025 Dec 24.

β-Hydroxy-β-Methylbutyrate enhances fast-twitch muscle and mitochondrial function, histopathology, and mTORC1 signalling in the mdx dystrophic mouse.

Nicholas Giourmas, Hannah Lalunio, Chuhui Wu, Ryan Marko Bagaric, Memphis Calzoni, Craig A Goodman, Alan Hayes.

  Duchenne muscular dystrophy (DMD) is one of the most severe forms of inheritable muscular dystrophies, caused by a genetic mutation resulting in the loss of dystrophin. Dystrophin loss initiates a cascade of negative mechanistic changes in skeletal muscle, such as disrupted protein homeostasis and mitochondrial dysfunction. Recent evidence suggests the leucine metabolite, β-Hydroxy-β-methylbutyrate (HMB), may improve physical function in DMD boys and improve aspects of the dystrophic phenotype in preclinical mdx mice. HMB has been shown to modulate protein turnover and mitochondrial function, both of which are dysregulated in DMD. Therefore, this study examined the effect of 3-weeks of HMB supplementation (0.75mg/g/day via drinking water), starting at 3-weeks of age in mdx mice. HMB-treated mdx mice exhibited increased full body grip strength and holding impulse, compared to mdx controls. HMB treatment also increased normalised muscle mass of the fast-twitch extensor digitorum longus (EDL) muscle, which coincided with increased average fiber size and improved absolute/specific in vitro force production. Moreover, HMB-treated EDL muscles displayed increased mitochondrial complex II succinate dehydrogenase activity, alongside upregulated markers of mTORC1 signalling (p70S6K1 and 4EBP1 phosphorylation), suggestive of increased protein synthesis. Lastly, muscle fibers isolated from HMB-treated mdx mice showed improved mitochondrial efficiency that was associated with increased maximal respiration, spare respiratory capacity and ATP synthesis. This study is the first to show HMB-induced improvements on in vitro and in vivo measures of mdx skeletal muscle force production that are coupled with improved mitochondrial function, suggesting that HMB may be a viable treatment option for DMD.

Keywords:  Duchenne Muscular Dystrophy (DMD); Extensor Digitorum Longus (EDL); Histopathology; Mitochondria; β-Hydroxy-β-Methylbutyrate (HMB)

DOI:  https://doi.org/10.1152/ajpcell.00722.2025