bims-mistre 2025-12-07 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–12–07
24 papers selected by
Ellen Siobhan Mitchell, MitoQ

Mitochondria at the crossroads of aging and cardiovascular disease.
The role of mitophagy in female reproductive system diseases: from molecular mechanisms to therapeutic strategies.
Molecular mechanisms of mitochondrial function in neurodegenerative diseases.
Exercise-mediated regulation of mitochondrial dynamics in aging muscle: implications for mitochondrial diseases.
Postmenopausal sarcopenia and Alzheimer's disease: The interplay of mitochondria, insulin resistance, and myokines.
Mechanisms and treatment modalities related to premature ovarian insufficiency in mitochondria: literature review.
Oxidative stress and antioxidant therapeutic mechanisms.
The role of gut dysbiosis and mitochondrial dysfunction in type 2 diabetes: Insights on pathogenesis, intervention and future perspective.
NADPH oxidase isoform NOX-2 deficiency affects mitochondrial oxygen consumption and metabolic flexibility.
Role of Dendritic Cells in Mediating the Effect of Growth Differentiation Factor 15 on Nonalcoholic Fatty Liver Disease: Insights From Causal Inference and Single-Cell Profiling.
The Vitamin D Receptor Ortholog Hr96 Modulates Neuronal and Mitochondrial Dynamics in a Drosophila Model of Alzheimer's Disease.
Phosphatidylserine Supplementation Improves Metabolic Liver Disease and Glycemic Control in the Presence of Suppressed Oxidative Glucose Metabolism.
Biological aging and lifespan in men and women using a Mendelian randomization study.
Editorial: Is insulin resistance the Eminence Grise of aging and non-communicable chronic diseases?
Platelets from Older Adults Exhibit Differences in Mitochondrial Function Associated with Impaired Glucose Metabolism.
Epigallocatechin-3-Gallate Provides Hepatoprotection Through Endoplasmic Reticulum Stress/TXNIP/NLRP3 Axis in Paracetamol-Induced Acute Liver Injury.
Harnessing hesperidin for brain metabolism: epigenetic signatures, cellular homeostasis, synaptic function, and neuroprotection in age-related diseases and neurodegenerative diseases.
Associations of growth differentiation factor 15 with kidney function in frail and pre-frail older individuals: the mediating role of inflammation and oxidative stress.
Combined myo-inositol and Banaba (1% Corosolic Acid) improve HOMA-IR and hepatic insulin extraction index in overweight and obese postmenopausal women.
Mitochondrial glutathione transporter SLC25A40 regulates macrophage cytokine production.
No causal links between estradiol and female's brain and mental health using Mendelian randomization.
Examining saliva proteomic dynamics in mitochondrial diseases from a perspective of intrinsic health.
The Evolution of Gallic Acid in Aged White Tea and Its Potential Anti-Aging Mechanisms: An Integrated Study Combining Network Pharmacology and Computer Simulation.
De Novo Hepatic Pyrimidine Synthesis Regulates Systemic Energy Homeostasis.

Life Sci. 2025 Nov 29. pii: S0024-3205(25)00763-5. [Epub ahead of print]385 124127

Mitochondria at the crossroads of aging and cardiovascular disease.

Olubodun Michael Lateef, Sodiq Fakorede, Chanel Harris, Adeola Mariam Lateef, Ayodeji Folorunsho Ajayi.

  Mitochondrial dysfunction plays a critical role in cardiovascular aging and is a key player in the development of cardiovascular diseases (CVDs) such as hypertension, arteriosclerosis, aneurysms, and heart failure. Aging disrupts mitochondrial function through impaired oxidative phosphorylation, excessive reactive oxygen species generation, mitochondrial DNA mutations, endoplasmic reticulum stress, mitochondrial enzyme dysregulation, and impaired calcium homeostasis. These alterations drive endothelial dysfunction, arterial stiffening, cardiac remodeling, and ultimately exacerbate age-related cardiovascular decline. Despite extensive research, the precise mechanisms by which mitochondrial aging impairs the function of endothelial cells, vascular smooth muscle cells, and cardiomyocytes remain poorly understood. Therefore, this review synthesizes current evidence on how aging-associated mitochondrial dysfunction contributes to endothelial dysfunction, arterial stiffening and remodeling, and cardiac dysfunction. It also outlines emerging pathophysiological mechanisms linking mitochondrial dysfunction to age-related CVDs, offering insights into potential therapeutic targets to promote cardiovascular health in aging populations. This review highlights key biomarkers of declining mitochondrial function to facilitate early diagnosis of CVD-related mitochondrial dysfunction. We show that aging disrupts key regulators of mitochondrial dynamics and quality control in the vasculature and heart across human studies and preclinical models of aging. Recent evidence indicates that impaired mitochondrial function in aging cardiomyocytes results in valvular degeneration, left ventricular hypertrophy, diastolic dysfunction, atrial fibrillation, and diminished exercise capacity. Therefore, understanding the pathophysiological mechanisms linking mitochondrial dysfunction to cardiovascular aging may guide the development of new therapeutic strategies for mitigating age-related cardiovascular decline in older adults.

Keywords:  Arterial disease; Cardiomyopathy; Cardiovascular aging; Endothelial dysfunction; Mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.lfs.2025.124127
Front Endocrinol (Lausanne). 2025 ;16 1645711

The role of mitophagy in female reproductive system diseases: from molecular mechanisms to therapeutic strategies.

Huiyi Zhao, Ying Wang, Han Han, Yue Jiang, Xiang Ji, Yuehui Zhang.

  Mitophagy is a catabolic mechanism that selectively degrades damaged mitochondria and precisely modulates mitochondrial content, thereby maintaining intracellular homeostasis under stress conditions. To date, most reviews on mitophagy have predominantly focused on neurodegenerative diseases, cardiovascular disorders, cancer, metabolic syndromes, and inflammation- or immune-related diseases. In recent years, accumulating evidence has highlighted the critical involvement of mitophagy in various physiological and pathological processes associated with female reproduction. This review systematically synthesizes existing evidence to elucidate the regulatory roles of mitophagy during the occurrence and development of follicles, oocyte fertilization, and embryo implantation, as well as its essential contributions to the pathogenesis of endometriosis, polycystic ovary syndrome, primary ovarian insufficiency, and ovarian aging. Furthermore, we outline current therapeutic strategies targeting mitophagy while emphasizing the potential value of traditional Chinese medicine. Our aim is to provide novel insights into the regulatory network and specific targets of mitophagy in female reproduction, facilitate clinical translation, and offer innovative approaches for managing female reproductive health.

Keywords:  female reproductive; female reproductive dysfunction; mitochondrial function; mitochondrial quality control; mitophagy

DOI:  https://doi.org/10.3389/fendo.2025.1645711
Mol Biol Rep. 2025 Dec 01. 53(1): 143

Molecular mechanisms of mitochondrial function in neurodegenerative diseases.

Heather M Wilkins, Simone Patergnani.

Mitochondria regulate cellular homeostasis and function in both neurons and glial cells, but molecular mechanisms are not fully understood. Recent advances have expanded our understanding of how mitochondrial dynamics, quality control, bioenergetics, redox regulation, and proteostasis contribute to neurodegenerative processes. The collection "Neuroscience: Mitochondrial Function in Neurons and Glia" highlights the pivotal role of mitochondria in energy production, redox signaling, calcium buffering, and apoptosis. Articles within this collection discuss the effects of mitochondria in neurodegeneration. Together, these studies emphasize ongoing challenges in defining cell type specific mitochondrial responses and point to the need for improved strategies to target mitochondrial dysfunction in neurological disease.

DOI: https://doi.org/10.1007/s11033-025-11303-7
Mol Cell Biochem. 2025 Dec 01.

Exercise-mediated regulation of mitochondrial dynamics in aging muscle: implications for mitochondrial diseases.

Chuanlong Zhang, Xiaoxia Zheng, Lijuan Xiang, Zhanguo Su.

  The deterioration of mitochondrial function is a hallmark of aging muscle and markedly accelerates the onset and progression of a range of mitochondrial diseases. Symptoms including limited mobility, persistent fatigue, and muscle weakness are often attributed to impaired mitochondrial dynamics, involving key mechanisms such as mitophagy, fusion, and fission. Exercise has been shown to positively influence mitochondrial health by regulating mitochondrial biogenesis, dynamics, and turnover. This review examines the exercise-induced modulation of mitochondrial processes in aging muscle and delineates its prospects as an intervention for managing mitochondrial diseases. We highlight the molecular mechanisms by which exercise orchestrates mitochondrial dynamics, augments organelle function, and triggers mitophagy-all of which are crucial for the preservation of muscle cell homeostasis. Furthermore, we explore how pivotal molecular pathways such as AMPK, PGC-1α, and SIRT1 regulate mitochondrial adaptations to exercise. This review also underscores the therapeutic promise of exercise in attenuating mitochondrial disease progression via enhanced mitochondrial quality control and improved muscle function. By integrating findings from mitochondrial science, gerontology, and exercise physiology, this review positions exercise as a crucial regulator of mitochondrial dynamics and a viable non-pharmacological strategy for maintaining muscle integrity in the contexts of aging and mitochondrial disease.

Keywords:  Aging muscle; Exercise; Mitochondrial diseases; Mitochondrial dynamics

DOI:  https://doi.org/10.1007/s11010-025-05441-6
Neurosci Biobehav Rev. 2025 Nov 29. pii: S0149-7634(25)00502-0. [Epub ahead of print]180 106501

Postmenopausal sarcopenia and Alzheimer's disease: The interplay of mitochondria, insulin resistance, and myokines.

Fardous Farhana, Most Arifa Sultana, Raksa Andalib Hia, Vijay Hegde.

  As life expectancy increases, cognitive impairments such as Alzheimer's disease (AD) create serious problems for older adults. Women regardless of ethnicity and age group, are disproportionately affected, accounting for two-thirds of AD cases, with post-menopausal women representing over 60 % of those affected. Sarcopenia, defined by gradual reduction of skeletal muscle mass, strength, and activities, is increasingly correlated with an elevated risk of cognitive decline in post-menopausal women. Menopause-related hormonal decline (particularly estrogen loss) and aging contribute to sarcopenia, characterized by muscle mitochondrial dysfunction, oxidative stress, and insulin resistance. This sarcopenia-driven reduction in muscle mass and functional capacity further reduces the production of myokines (e.g., BDNF, irisin), impairing neuronal proliferation, adult neurogenesis, and spatial learning/memory. These pathophysiological changes show a contributing link between sarcopenia and AD progression in post-menopausal women. This review is unique in that it discusses the triangular interplay between menopause, sarcopenia, and AD, offering an integrated mechanistic framework that links hormonal decline, muscle loss, and neurodegeneration. We aim to clarify the pathophysiological causes behind the muscle-brain axis and suggest viable treatment approaches to slow down sarcopenia and cognitive deterioration in postmenopausal women based on current evidence. The formulation of targeted strategies for enhancing the quality of life and lessening healthcare expenditures in this expanding population depends on the advancement of understanding this complex interconnection between menopause, sarcopenia and cognition.

Keywords:  Alzheimer’s disease; Insulin resistance; Menopause; Mitochondrial dysfunction; Myokines; Oxidative stress; Sarcopenia

DOI:  https://doi.org/10.1016/j.neubiorev.2025.106501
J Ovarian Res. 2025 Dec 06.

Mechanisms and treatment modalities related to premature ovarian insufficiency in mitochondria: literature review.

Huihui Li, Xinyu Zhu, Ruotong Ju, Puhua Zhang, Tingting Xue, Shu Wang, Ruixiang Zhu, Jiali Luo, Xuan Jing, Xiangrong Cui.

  Premature ovarian insufficiency (POI) is a common, heterogeneous disorder that affects up to 3.5% of women under 40 years of age and is defined by oligo/amenorrhoea, hypo-oestrogenism, and markedly elevated gonadotrophin levels. POI substantially increases risks for infertility, osteoporosis, cardiovascular disease, and psychological morbidity; however, its precise aetiology remains elusive, and current therapies rarely restore lasting ovarian function. This review synthesizes recent molecular, cellular, and animal data to clarify how six facets of mitochondrial dysregulation: oxidative stress, imbalanced dynamics (fusion/fission/mitophagy), defective biogenesis, altered mitochondrial DNA (copy-number and mutation), mitochondrial membrane potential, and disrupted electron-transport-chain activity-contribute to accelerated oocyte apoptosis, granulosa-cell dysfunction, and premature follicle loss. We further evaluate emerging mitochondria-targeted interventions, including small-molecule antioxidants, modulators of mitochondrial dynamics, biogenesis activators, autophagy regulators, mtDNA-protective agents, and innovative strategies such as mitochondrial transplantation. This article aims to systematically elaborate the mechanism of mitochondrial dysfunction in POI, summarize the treatment strategies for mitochondria, and provide a theoretical basis for clinical intervention.

Keywords:  Mechanism; Mitochondria; Premature ovarian insufficiency (POI); Prevention and treatment

DOI:  https://doi.org/10.1186/s13048-025-01915-9
Pharmacol Ther. 2025 Nov 30. pii: S0163-7258(25)00174-3. [Epub ahead of print] 108962

Oxidative stress and antioxidant therapeutic mechanisms.

Hengrui Liu, Yaqi Jiao, Peng-Chao Wang, Yingjie Chen, Maokai Xu, Xiaojuan Zhang, Xiaochun Zheng, Zhenshan Yang.

  Oxidative stress is now understood as a disturbance in the cellular redox balance, involving the accumulation of reactive oxygen, nitrogen, and other reactive species beyond the capacity of antioxidant defenses, with effects that range from essential redox signaling to harmful oxidative damage. Reactive oxygen and nitrogen species are generated from both endogenous metabolic processes and exogenous environmental factors. While controlled levels of oxidative stress contribute to cellular signaling and homeostasis, excessive oxidative damage can lead to pathological conditions, including cardiovascular diseases, diabetes, neurodegenerative disorders, inflammatory conditions, and cancer. To counteract oxidative damage, the body employs a complex antioxidant defense system, comprising endogenous enzymatic and non-enzymatic mechanisms, as well as exogenous dietary antioxidants. Therefore, understanding the regulatory pathways and mechanisms of antioxidants is essential for exploring their role in disease prevention, aging, and immune function. This review provides a comprehensive analysis of oxidative stress, its impact on cellular function, and its involvement in disease pathogenesis. Furthermore, it discusses current therapeutic intervention mechanisms, including dietary strategies, pharmacological antioxidants, and clinical trials evaluating antioxidant efficacy. Finally, emerging research directions, such as novel antioxidant compounds, gene therapy, and personalized antioxidant treatments, are highlighted as potential avenues for future exploration.

Keywords:  Antioxidants; Disease pathogenesis; Oxidative stress; Reactive oxygen species; Therapeutic targets

DOI:  https://doi.org/10.1016/j.pharmthera.2025.108962
Biomed Pharmacother. 2025 Dec 04. pii: S0753-3322(25)01040-6. [Epub ahead of print]193 118846

The role of gut dysbiosis and mitochondrial dysfunction in type 2 diabetes: Insights on pathogenesis, intervention and future perspective.

Xuefei Yu, Mingxiao Li, Houkai Li.

  Type 2 diabetes (T2D) is a typical metabolic disease which is attributed to genetic and environmental factors. Emerging evidence has highlighted that either gut dysbiosis or mitochondrial dysfunction plays critical roles in the development of T2D through various ways. After searching preclinical and clinical studies, our review concludes that gut dysbiosis contribute to T2D through gut metabolites-induced inflammation, dysregulation of glucose homeostasis and the change of β-cell evolution. Moreover, we found out that the overproduction of oxidative stress, disruption of energy metabolism, mitochondrial dynamic network and mitochondrial permeability transition are major mechanisms which contribute to the development of T2D by mitochondrial dysfunction. We particularly focused on summarizing the advances of how gut dysbiosis and mitochondrial dysfunction contributed to T2D development, respectively, and elaborating their interplay in central and peripheral organs. Moreover, the latest strategies on T2D management were also discussed, in which modulation on gut microbiota and mitochondrial function were primarily included, as well as perspectives on future investigations.

Keywords:  gut microbiota; metabolic disease; microbial metabolite; mitochondria; type 2 diabetes

DOI:  https://doi.org/10.1016/j.biopha.2025.118846
Redox Biol. 2025 Nov 26. pii: S2213-2317(25)00461-6. [Epub ahead of print]88 103948

NADPH oxidase isoform NOX-2 deficiency affects mitochondrial oxygen consumption and metabolic flexibility.

Kannathasan Thetchinamoorthy, Diana Wierzbicka, Emilia Waraksa-Zasada, Michalina Kazek, Adrian Konopko, Mariusz Z Ratajczak, Magdalena Kucia.

  Our recent study showed that the intracellular pattern recognition receptor Nlrp3 inflammasome, activated by reactive oxygen species (ROS), regulates metabolism in hematopoietic cells by maintaining proper "tonic activation" of the electron transport chain (ETC) in mitochondria. Therefore, we asked whether a deficiency in the expression of NADPH oxidase isoform NOX-2, a primary source of ROS in hematopoietic cells, would similarly affect mitochondrial function and metabolic adaptation to stress. In this study, we examined how NOX-2 influences ETC, redox balance, and glycolytic adaptation in lineage-negative Sca-1+c-Kit+ (SKL) bone marrow stem cells from wild-type (WT) and NOX-2 knockout (NOX2-KO) mice. Metabolic testing revealed that NOX2-KO cells have impaired mitochondrial respiration, lower ATP production, and reduced spare respiratory capacity. When exposed to hydrogen peroxide, NOX2-KO cells failed to activate a mitochondrial stress response and instead relied more on anaerobic glycolysis. Treatment with extracellular ATP (eATP), the most abundant signaling alarmin, increased ROS levels in WT cells but not in NOX2-KO cells, emphasizing eATP-NOX-2's role in redox regulation during stress conditions. Proteomic analysis identified proteins differentially expressed related to hypoxia, glycolysis, and oxidative stress response between WT and NOX2-KO SKL cells. These results demonstrate NOX-2 as a key regulator of mitochondrial function and metabolic flexibility in hematopoietic stem cells, highlighting its importance in maintaining redox balance during stress conditions.

Keywords:  Hematopoietic stem and progenitor cells (HSPCs); Mitochondrial metabolism; NOX-2; Oxidative stress; Purinergic signaling; Reactive oxygen species (ROS); Redox signaling

DOI:  https://doi.org/10.1016/j.redox.2025.103948
Mediators Inflamm. 2025 ;2025 1153091

Role of Dendritic Cells in Mediating the Effect of Growth Differentiation Factor 15 on Nonalcoholic Fatty Liver Disease: Insights From Causal Inference and Single-Cell Profiling.

Tao Yao, Peng Zheng, Zhe-Ning Wang, Luo-Xiang Fang, Yu-Huan Wu, Yuan-Nan Lin.

   Background: Nonalcoholic fatty liver disease (NAFLD) represents one of the most prevalent chronic liver conditions worldwide. Previous studies have highlighted an association between circulating growth differentiation factor 15 (GDF-15) levels and NAFLD, as well as the involvement of immune cells in its pathogenesis and progression. However, the causal relationships remain unclear.
Methods: We obtained summary-level data for circulating GDF-15 levels, NAFLD, and 731 immune cell phenotypes from large-scale genome-wide association studies (GWAS) and the FinnGen database. Mendelian randomization (MR) analysis was employed to explore the causal relationship between circulating GDF-15 levels and NAFLD. Additionally, a two-step MR approach was utilized to identify and assess the mediatory role of immune cells in this association. Finally, single-cell RNA sequencing analysis (scRNA-seq) was performed to validate the proportions of CD123+ dendritic cell (DC) subsets in NAFLD progression.
Results: Two-sample MR analysis revealed that elevated levels of GDF-15 are associated with an increased risk of NAFLD (OR = 1.16; 95% confidence interval [CI] = 1.03-1.30; p=0.017), and replication analysis further confirmed the stability of these findings (OR = 1.10; 95% CI = 1.01-1.20; p=0.037). Mediation analysis identified that CD123 on plasmacytoid DCs (DCs), CD123 on CD62L+ plasmacytoid DCs, CD80 on plasmacytoid DCs, and CD80 on CD62L+ plasmacytoid DCs mediate the causal effect of GDF-15 on NAFLD. Sensitivity analyses and bidirectional MR further ensured the robustness of these findings. Single-cell analysis further validated these results.
Conclusions: Our findings propose a causal relationship between GDF-15 and NAFLD mediated by DCs, offering novel insights for potential therapeutic and preventive strategies for NAFLD.

Keywords:  Mendelian randomization; growth differentiation factor 15; immune cells; mediation analysis; nonalcoholic fatty liver disease

DOI:  https://doi.org/10.1155/mi/1153091
Mol Neurobiol. 2025 Dec 03. 63(1): 238

The Vitamin D Receptor Ortholog Hr96 Modulates Neuronal and Mitochondrial Dynamics in a Drosophila Model of Alzheimer's Disease.

Guilherme Gischkow Rucatti, Francisco Muñoz-Carvajal, Nicole Sanhueza, Sebastian Oyarce-Pezoa, Yesid Cuesta-Astroz, Leandro Murgas, Melissa Caru-Ruiz, Alberto J M Martin, Melissa Calegaro-Nassif, Carol D SanMartín, Mario Sanhueza.

  Alzheimer's disease (AD) is the most common cause of dementia, characterized by amyloid-β (Aβ42) accumulation, with a progressive breakdown of synapsis connection, neuronal death, and cognitive loss. Mitochondrial impairment emerges early in AD, preceding cognitive symptoms and contributing to disease progression. Vitamin D (VD) is a neurosteroid that acts as a transcription factor through its nuclear receptor, the vitamin D receptor (VDR), playing a central role in metabolic control. The Drosophila VDR ortholog, hormone receptor 96 (Hr96), is known to regulate xenobiotic protection and energy metabolism, but its neuronal functions and impact on AD pathomechanisms are poorly understood. Here, we investigate Hr96's role in neuronal and mitochondrial homeostasis, hypothesizing that its signaling modulates mitochondrial dynamics and mitigates neurodegeneration in AD. We identified Hr96-regulated genes involved in lipid metabolism, oxidative stress, and mitochondrial dynamics. Modulation of Hr96 expression in fly neurons revealed that knockdown had minimal early effects but led to reduced lifespan and motor decline, while overexpression induced metabolic imbalances, circadian disruptions, and premature mortality. Mitochondrial analyses showed that Hr96 overexpression affected functionality, increased fragmentation, and upregulated fission markers, such as Drp1, suggesting a role in mitochondrial dynamics. Then, when we studied an AD fly model, Hr96 loss exacerbated Aβ42-induced neurotoxicity, reducing lifespan and motor performance. Conversely, Hr96 overexpression extended lifespan under Aβ42 toxicity but did not affect neuromuscular junction bouton number and size. Furthermore, when mitochondrial parameters were analyzed, overexpression of this gene suppresses Aβ42-linked mitochondrial phenotypes to levels closer to wild type. These findings unveil Hr96 as a potential modulator of mitochondrial and neuronal homeostasis, and that in the context of a time-dependent insult such as Aβ42 accumulation, its overexpression is protective. Further studies are needed to elucidate its role in mitochondrial regulation and transcriptional networks, paving the way for therapeutic strategies targeting mitochondrial dysfunction in neurodegeneration.

Keywords:  Alzheimer’s disease; Drosophila; Hr96; Vitamin D

DOI:  https://doi.org/10.1007/s12035-025-05502-3
Diabetes. 2025 Dec 05. pii: db250588. [Epub ahead of print]

Phosphatidylserine Supplementation Improves Metabolic Liver Disease and Glycemic Control in the Presence of Suppressed Oxidative Glucose Metabolism.

Li Dong, Sihan Lin, John Slavin, Satya Gunnam, Zhili Cheng, Shuai Nie, Michael G Leeming, Nicholas A Williamson, Magdalene K Montgomery.

Type 2 diabetes and obesity are commonly accompanied by metabolic dysfunction-associated steatotic liver disease (MASLD), increasing the risk of developing metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis. The early stages of MASLD are characterized by dysfunctional lipid metabolism, including remodeling of the hepatic lipidome. In this context, reductions in hepatic phosphatidylserine (PS) have been associated with increased hepatic steatosis, inflammation, and fibrosis. In this study, we investigated the impact of dietary PS supplementation on liver function and systemic metabolic homeostasis in mice with hepatic steatosis and MASH. Taking advantage of the MUP-uPA mouse model, including wild-type mice with hepatic steatosis and MUP-uPA mice with MASH and fibrosis, we showed that PS supplementation reduces hepatic triglyceride accumulation, inflammation, and fibrosis in male MUP-uPA mice. Supporting these data, PS supplementation suppressed fibrogenic gene expression in LX-2 hepatic stellate cells. We further showed that PS supplementation improved glycemic control and insulin sensitivity in male and female mice, which was associated with enhanced insulin signaling in muscle and liver, despite a pronounced suppression of glycolysis, glucose oxidation, and glycogen breakdown in liver, muscle, and/or adipose tissue. Metabolic flux analysis suggested a shift in substrate use, favoring fatty acid metabolism, particularly in muscle, while further pointing to marked improvements in mitochondrial function and oxidative capacity. These findings indicate that PS exerts multifaceted benefits by improving both MASH and whole-body glucose homeostasis, independent of conventional oxidative glucose metabolism. Our results support further investigation into dietary PS as a potential complementary strategy for MASH and glycemic control.
ARTICLE HIGHLIGHTS: The prevalence of metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes is increasing. We show that dietary phosphatidylserine (PS) supplementation reduces hepatic lipid accumulation, inflammation, and liver fibrosis, while further improving blood glucose control and insulin sensitivity in mice with MASH and insulin resistance. Improvements in glycemic control are present despite suppression of glycolysis, glucose oxidation, and glycogen breakdown in liver, skeletal muscle, and/or adipose tissue. In contrast, oxidative lipid metabolism and overall mitochondrial function are enhanced in skeletal muscle.

DOI: https://doi.org/10.2337/db25-0588
Hum Genomics. 2025 Dec 05. 19(1): 143

Biological aging and lifespan in men and women using a Mendelian randomization study.

C M Schooling, Shun Li, Zhu Liduzi Jiesisibieke.

   PURPOSE: Identification of targets of intervention to promote lifespan is crucial given lifespan is an important measure of public health. Telomere length and epigenetic clocks are key biological markers of aging, whether they are targets of intervention in men or women is unclear. We examined their associations with sex-specific lifespan in a Mendelian randomization study.
METHODS: We used genetic summary statistics of telomere length and lifespan (parental attained age and survival to recruitment) from the UK Biobank (n = ~ 0.5 million, mean age = ~ 57 years) and of epigenetic clocks (GrimAge, PhenoAge, HannumAge and Intrinsic epigenetic age acceleration) from a meta-analysis of 28 cohorts (n = 34,710). Using this data, we employed two-sample MR to estimate the causal effect of each aging biomarker on lifespan in men and women. Estimates were obtained using inverse variance weighting with sensitivity analysis.
RESULTS: There was no evidence that telomere length was associated with lifespan in men (0.17 years per standard deviation of log telomere length, 95% confidence interval (CI) -0.54 to 0.88, survival - 0.17 years, 95% CI -0.39 to 0.05) or in women (0.04, 95% CI -0.88 to 0.96), although telomere length was associated with poorer survival to recruitment in women (survival - 0.24 years, 95% CI -0.44 to -0.03). Associations of epigenetic clocks with lifespan and survival were null in both men and women. Sensitivity analysis gave similar estimates.
CONCLUSIONS: Telomere length and commonly used epigenetic clocks may not be an appropriate target for promoting lifespan. Instead, efforts to develop interventions for aging should target causal drivers of lifespan.

Keywords:  Aging; Epigenetic clock; Lifespan; Mendelian randomization; Sex-difference; Telomere length

DOI:  https://doi.org/10.1186/s40246-025-00852-4
Front Endocrinol (Lausanne). 2025 ;16 1735592

Editorial: Is insulin resistance the Eminence Grise of aging and non-communicable chronic diseases?

Dzilda Velickiene, Izabela Szymczak-Pajor, Aivaras Ratkevicius.



Keywords:  aging; cardiovascular diseases; insulin resistance; non-communicable chronic diseases; non-insulin-based surrogate indices for insulin resistance

DOI:  https://doi.org/10.3389/fendo.2025.1735592
Clin Sci (Lond). 2025 Nov 28. pii: CS20242841. [Epub ahead of print]

Platelets from Older Adults Exhibit Differences in Mitochondrial Function Associated with Impaired Glucose Metabolism.

Gargi Mahapatra, Zhengrong Gao, James Bateman, Samuel Neal Lockhart, Jaclyn Bergstrom, Jemima Elizabeth Piloso, Suzanne Craft, Anthony J A Molina.

  Impaired glucose tolerance (IGT) and insulin resistance, including prediabetes and diabetes, increases risk of developing age-related disorders, such as cardiovascular disorders, kidney disorders, and Alzheimer's disease (AD). We analyzed mitochondrial bioenergetics of platelets collected from 208 adults, 55 years and older, with IGT and insulin resistance and without (normoglycemic, NG). Platelets from IGT participants exhibited unique mitochondrial bioenergetic profiles exemplified by higher mitochondrial respiration compared to NG. IGT platelets exhibited higher glucose-dependent maximal (Max) and spare respiratory (SRC) capacities, and higher fatty acid oxidation (FAO)-dependent maximal coupled (MaxOXPHOS) and uncoupled (MaxETS) respiration, compared to NG. Correlating mitochondrial bioenergetics from all 208 participants with measures of glucose tolerance (oral glucose tolerance test values measured 120 mins after glucose administration (OGTT_120), and oral glucose tolerance test area under the curve (OGTT_AUC)), and historical glucose measures (hemoglobin A1 (HbA1c)) revealed significant positive associations. Most associations were unaltered with age, sex, and BMI adjustments. Examining NG and IGT participants separately, we found platelet respiration and HbA1c exhibited positive association in NG participants. Significant positive associations emerged between platelet SRC, FAO, FAO+CI (oxygen flux due to fatty acid oxidation + complex I activities) and HbA1c. No significant associations were observed in the IGT group. Given the utilization of blood based mitochondrial bioenergetic profiling strategies in clinical research, this work provides new insights into the clinical features of insulin resistance that can impact platelet mitochondrial bioenergetics.

Keywords:  Platelets; diabetes; impaired glucose tolerance; insulin resistance; mitochondrial bioenergetics; normoglycemia; type 2 diabetes

DOI:  https://doi.org/10.1042/CS20242841
Basic Clin Pharmacol Toxicol. 2026 Jan;138(1): e70155

Epigallocatechin-3-Gallate Provides Hepatoprotection Through Endoplasmic Reticulum Stress/TXNIP/NLRP3 Axis in Paracetamol-Induced Acute Liver Injury.

Nagihan Demirtas, Busra Sahin Mazlumoglu, Nevra Aydemir Celep, Elif Cadirci, Zekai Halici, Saziye Sezin Palabiyik-Yucelik.

  Epigallocatechin-3-gallate (EGCG) is a polyphenolic compound with strong antioxidant properties and is abundantly found in green tea. We investigated how EGCG affects the liver injury of high-dose paracetamol in this study. In our study, 56 rats were divided into seven groups (n = 8): healthy control, EGCG (100 mg/kg), paracetamol (2 g/kg), paracetamol + EGCG 25 (2 g/kg + 25 mg/kg), paracetamol + EGCG 50 (2 g/kg + 50 mg/kg), paracetamol + EGCG 100 (2 g/kg + 100 mg/kg) and paracetamol + N-acetyl cysteine (NAC, 2 g/kg + 140 mg/kg). Our findings suggest that high-dose paracetamol induces liver injury through endoplasmic reticulum (ER) stress and that EGCG alleviates liver injury by attenuating ER stress-induced inflammasome signalling.

Keywords:  (–)‐epigallocatechin‐3‐gallate (EGCG); endoplasmic reticulum stress; inflammasome; liver; paracetamol

DOI:  https://doi.org/10.1111/bcpt.70155
Front Nutr. 2025 ;12 1706146

Harnessing hesperidin for brain metabolism: epigenetic signatures, cellular homeostasis, synaptic function, and neuroprotection in age-related diseases and neurodegenerative diseases.

Wei Zhao, Wenwu Hong, Yingying Cao.

  Age-associated neurodegenerative disorders constitute a considerable global health concern, distinguished by a progressive deterioration in cognitive function, synaptic impairment, and disrupted cellular homeostasis. Recent research has identified hesperidin (HSP), a bioactive flavonoid predominantly present in citrus fruits, as a potentially valuable neurotherapeutic compound due to its diverse molecular mechanisms of action. This review aims to consolidate existing literature regarding HSP's ability to influence epigenetic modifications, augment synaptic plasticity, and restore cellular equilibrium in the aging central nervous system. We investigate the manner in which HSP affects critical epigenetic markers, such as DNA methylation and histone modifications. Therefore it modulates gene expression essential for neuroprotection and lifespan extension. Furthermore, we examine the role of HSP in the preservation of synaptic integrity and neurotransmission, which are crucial for cognitive resilience in the face of age-related deterioration. The review further clarifies the antioxidant and anti-inflammatory properties of HSP, which together promote neuronal viability and alleviate neurodegenerative pathology. By synthesizing mechanistic insights and preclinical evidence, this article underscores the potential of HSP as a natural compound for both the prevention and adjunctive treatment of neurodegenerative disorders, thereby advocating for translational research aimed at realizing its full therapeutic efficacy.

Keywords:  age-related diseases; brain metabolism; hesperidin; neuroprotection; synaptic function

DOI:  https://doi.org/10.3389/fnut.2025.1706146
Eur J Med Res. 2025 Dec 04.

Associations of growth differentiation factor 15 with kidney function in frail and pre-frail older individuals: the mediating role of inflammation and oxidative stress.

Chi Zhang, Anying Bai, Yuting Kang, Qiang Gao, Jie Zhang, Yushan Zhang, Zehong Huo, Yingqi Zhao, Hong Shi, Ji Shen, Ping Zeng.

   BACKGROUND: This cross-sectional investigation aimed to investigate the association of plasma Growth Differentiation Factor 15 (GDF-15) with kidney function in frail and pre-frail older individuals, and to further test the mediating roles of inflammation and oxidative stress.
METHODS: 483 older adults (71.64 ± 6.07 years) with frailty or pre-frailty status were included. Plasma GDF-15 was measured using enzyme-linked immunosorbent assay. An estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2 was indicated as kidney dysfunction. Spearman correlation coefficients and multivariate logistic regression models were used to analyze the relationship between GDF-15 and kidney function. Structural equation modeling was used to explore the mediating factors.
RESULTS: Both the absolute concentration and the ln-transformed concentration of GDF-15 were significantly negatively correlated with eGFR (both P < 0.001). In the multivariate logistic analysis, the odds ratio (OR) of kidney dysfunction for per 1-SD increase in GDF-15 was 1.36 (95% CI 1.04-1.78). Compared with the first quartile group of GDF-15, the OR of kidney dysfunction in the third quartile group was 2.74 (95% CI 1.44-5.23, P = 0.002). Tumor necrosis factor, malondialdehyde, and glutathione peroxidase mediated the relationship between GDF-15 and eGFR, with mediating proportions of 7.23%, 8.41%, and 9.83%, respectively.
CONCLUSIONS: Our findings suggest that high levels of GDF-15 are associated with lower eGFR in frail and pre-frail older individuals. GDF-15 may be related to kidney function through its involvement in inflammatory and oxidative stress responses.

Keywords:  Frailty; Glomerular filtration rate; Growth differentiation factor 15; Mediation analysis

DOI:  https://doi.org/10.1186/s40001-025-03619-8
Gynecol Endocrinol. 2025 Dec 31. 41(1): 2596417

Combined myo-inositol and Banaba (1% Corosolic Acid) improve HOMA-IR and hepatic insulin extraction index in overweight and obese postmenopausal women.

Christian Battipaglia, Valeria Vescovi, Martina Foschi, Benedetta Righi, Alessandra Sponzilli, Veronica Setti, Maria Laura Rusce, Alessandro D Genazzani.

   OBJECTIVE: To assess the effects of a 12-week combined treatment with myo-inositol (2 g) and Banaba extract (48 mg) standardized to 1% corosolic acid (MBN) on insulin resistance (HOMA-IR) and hepatic insulin extraction index (HIEI) in overweight and obese postmenopausal women.
METHODS: We conducted a retrospective observational study including 31 postmenopausal women (mean age 51 ± 1.2 years) attending the Gynecological Endocrinology Center of Modena, Italy. All patients received daily supplementation with MBN for 12 weeks. Hormonal and metabolic parameters-including fasting glucose, insulin, C-peptide, and HOMA-IR-were assessed before and after treatment. In addition, an oral glucose tolerance test (OGTT) was performed at both time points, with glucose, insulin, and C-peptide curves measured and corresponding area under the curve (AUC) values at 240 minutes calculated. HIEI was calculated as the insulin/C-peptide ratio. Data were analyzed globally and then stratified by family history of diabetes.
RESULTS: After treatment, fasting insulin, HOMA-IR, and HIEI were significantly reduced. The OGTT showed a 23.5% decrease in glucose AUC, with greater reductions in insulin AUC (-42%) compared to C-peptide AUC (-16.8%), suggesting enhanced hepatic insulin clearance. Patients with a family history of diabetes showed reductions in insulin and C-peptide, while those without showed only a decrease in insulin and HIE, with no changes in C-peptide.
CONCLUSIONS: Combined MBN supplementation improved insulin sensitivity and hepatic insulin clearance in overweight and obese postmenopausal women, with particularly pronounced effects in those with a family history of diabetes. These findings underscore the potential of targeted integrative strategies to mitigate insulin resistance in this population.

Keywords:  Banaba; HIEI; HOMA-IR; Myo-inositol; corosolic acid; hepatic insulin extraction index; insulin resistance; menopause

DOI:  https://doi.org/10.1080/09513590.2025.2596417
Sci Rep. 2025 Dec 01. 15(1): 42939

Mitochondrial glutathione transporter SLC25A40 regulates macrophage cytokine production.

Maureen Yin, Eva M Palsson-McDermott, Órlaith C Henry, Ziqian Ge, Juliana E Toller-Kawahisa, Yukun Min, Anne F McGettrick, Adam L Gordon, Stella B Heffernan, Laura Marrone, Bryan P Marzullo, Katherine L Eales, Sally A Clayton, Daniel A Tennant, Richard K Porter, Luke A J O'Neill.

  Mitochondrial glutathione (mtGSH) supports iron-sulfur cluster (ISC) stability in the electron transport chain (ETC). Here we have investigated the role of the mtGSH transporter SLC25A40 in macrophage activation. SLC25A40 is present in both murine and human macrophages and its expression was increased by LPS treatment. Reducing SLC25A40 expression using siRNA destabilized ISC-rich ETC proteins and elevated mitochondrial and cellular reactive oxygen species (ROS). It also induced expression of the genes Gclc and Gclm, which are involved in GSH biosynthesis. SLC25A40 deficiency also diminished IL-1β and IL-10 production at the transcriptional level in response to LPS. As a result, the production of mature IL-1β was decreased following activation of NLRP3 by nigericin or ATP, with no effect on pyroptosis. Depleting mtGSH with mitochondrially-targeted CDNB phenocopied these defects, whereas supplementation with a cell-permeable GSH ester partially restored pro-IL-1β production. Together, these data identify SLC25A40 as a key regulator that sustains ETC integrity to promote cytokine production, revealing a previously unrecognized role for the SLC25A40-mtGSH axis in coupling mitochondrial redox control to macrophage activation.

Keywords:  Cytokine; Electron transport chain (ETC); Glutathione (GSH); Macrophage immunometabolism; Mitochondria; SLC25A39/40

DOI:  https://doi.org/10.1038/s41598-025-30333-6
Nat Commun. 2025 Dec 05. 16(1): 10915

No causal links between estradiol and female's brain and mental health using Mendelian randomization.

Hannah Oppenheimer, Dennis van der Meer, Louise S Schindler, Arielle Crestol, Alexey Shadrin, Ole A Andreassen, Lars T Westlye, Ann-Marie G de Lange, Claudia Barth.

The role of estradiol in depression and Alzheimer's disease - brain disorders that disproportionately affect females - is debated. Results from observational studies are inconsistent and limited by confounding and reverse causation. To overcome these limitations, we perform two-sample Mendelian randomization. We run genome-wide association studies on sex-specific brain age gap, a proxy of brain health, and female-specific estradiol levels using data from the UK Biobank. We test for causal links between genetically-predicted factors related to estradiol exposure (estradiol levels in pre- and postmenopausal samples, reproductive span, age at menarche, age at menopause, number of childbirths) and brain age gap, Alzheimer's disease and depression as outcomes. We replicate our analyses on estradiol levels in males. Here, we find no significant associations between estradiol exposure and brain health across samples and robust methods, indicating an absence of constant causal effects and suggesting that hormonal fluctuations may drive links between estradiol and brain health.

DOI: https://doi.org/10.1038/s41467-025-65878-7
Sci Rep. 2025 Dec 02. 15(1): 43031

Examining saliva proteomic dynamics in mitochondrial diseases from a perspective of intrinsic health.

Jiaying Zhao, Bowen Xu, Tianhui Huang, Sewanou Hermann Honfo, Caroline Trumpff, Martin Picard, Alan A Cohen, Molei Liu.

Mitochondrial disease (MitoD), a clinical condition caused by genetic mitochondrial defects, affects cellular energy transformation and alters multiple dimensions of health. Recently, we collected a longitudinal saliva proteomics data set consisting of six healthy controls and six MitoD subjects throughout the awakening response process. We undertook three independent unsupervised or inferential approaches to characterize proteome dynamics and assessed their ability to separate MitoD individuals from controls. First, we designed a permutation test to detect the global difference in the proteomic co-regulation structure between healthy and unhealthy subjects. Second, we performed non-linear embedding and cluster analysis on elasticity to capture a more complicated relationship between health and the proteome. Third, we developed a machine learning algorithm to extract low-dimensional representations of the proteome dynamic and use them to cluster subjects into healthy and unhealthy groups without any knowledge of their true status. All three methods showed clear differences between MitoD individuals and controls. Our results revealed a significant and consistent association between MitoD status and the saliva proteome at multiple levels during the awakening response, including its dynamic change, co-regulation structure, and elasticity. Pipelines such as those shown here are the first step toward establishing interpretable and accurate framework for detecting signals related to mitochondrial disease progression from proteome dynamics.

DOI: https://doi.org/10.1038/s41598-025-23879-y
Food Sci Nutr. 2025 Dec;13(12): e71246

The Evolution of Gallic Acid in Aged White Tea and Its Potential Anti-Aging Mechanisms: An Integrated Study Combining Network Pharmacology and Computer Simulation.

Yanming Tuo, Xiaofeng Lu, Qingying Song, Ruiqi Huang, Jiapeng Huang, Huan Sun, Ningkai Liao, Yutao Shi, Liangyu Wu, Jinke Lin, Yunfei Hu.

  Aging, characterized by a gradual decline in physiological function, is a major risk factor for chronic diseases. White tea, one of China's traditional tea types, exhibits various health benefits due to its unique chemical composition, with its anti-aging potential drawing increasing attention. Gallic acid (GA), one of the important bioactive components in white tea, possesses antioxidant and anti-inflammatory properties, but its anti-aging mechanisms remain unclear. In this study, high-performance liquid chromatography was used to analyze the evolution of GA content and to determine the antioxidant capacity of aged white tea. Results revealed that the GA content increased with storage time, accompanied by a corresponding enhancement in the antioxidant potency composite index (APC). Network pharmacology predicted 40 potential anti-aging targets of GA, and protein-protein interaction network analysis identified six key targets (MAOA, PTGS2, BCL2, APP, IGF1R, SERPINE1). Functional enrichment analysis indicated that the anti-aging effects of GA are mediated through multiple pathways, particularly those related to oxidative stress. Molecular docking results demonstrated that GA could bind effectively to the six key targets via hydrogen bonding and hydrophobic interactions. Furthermore, molecular dynamics simulations confirmed the binding stability of GA with MAOA, PTGS2, and BCL2. This study systematically elucidates the evolution of GA in aged white tea and its potential anti-aging mechanisms, providing a theoretical basis for the development of GA and aged white tea as functional anti-aging additives.

Keywords:  aging; gallic acid; molecular docking; molecular dynamics simulation; network pharmacology; tea

DOI:  https://doi.org/10.1002/fsn3.71246
bioRxiv. 2025 Nov 18. pii: 2025.11.18.689117. [Epub ahead of print]

De Novo Hepatic Pyrimidine Synthesis Regulates Systemic Energy Homeostasis.

Ling Fu, Pradnya H Patil, Pengfei Zhang, Ignacio Norambuena-Soto, Qiutang Xiong, Yin Wang, Chelsea Jang, Kevin Wang, Yunqian Peng, Lu Ding, Patrick Fueger, Lihua Jin, Wendong Huang, Philip L Lorenzi, Lin Tan, Markus Kalkum, Philipp E Scherer, Zhao V Wang, Yingfeng Deng.

Fasting blood uridine is increased in obesity and type 2 diabetes (T2D), but the significance of hepatic uridine biosynthesis to the etiology of both remains elusive. We found that de novo pyrimidine synthesis in the liver is reduced by fasting and diet-induced obesity, while suppression of hepatic pyrimidine synthesis promotes obesity and insulin resistance. The metabolic sequalae of hepatic pyrimidine synthesis suppression, however, is not associated with altered plasma uridine concentration. Instead, it is associated with an increased hepatic glucose production and a decreased hepatic insulin clearance, two key functions of hepatocytes in regulating systemic energy homeostasis. We found that enhanced gluconeogenesis is the primary reason for increased hepatic glucose production. Moreover, uridine, which was maintained stable in the circulation by adipose tissue and the liver, preferentially shut down pyrimidine synthesis in hepatocytes but not adipocytes at blood concentrations that occur with fasting. Remarkably, uridine, at fasting levels, increases gluconeogenesis further in hepatocytes when de novo pyrimidine synthesis is suppressed, indicating a synergistical action of uridine and its biosynthesis pathway in promoting hepatic glucose production, a mechanism highly relevant to the pathophysiology of insulin resistance in obesity. Theologically, maintenance of blood uridine within the narrow range protects mammals from high-rate spontaneous tumorigenesis. Since obesity promotes an increase in blood uridine from adipocytes, suppressing uridine synthesis in hepatocytes becomes a critical response to lower spontaneous tumorigenesis. Pyrimidine synthesis suppression in hepatocytes, however, promotes gluconeogenesis and ultimately triggers obesity and T2D. These findings suggest a new paradigm for the etiology of metabolic deterioration in diet-induced obesity, in which perturbations in uridine promotes obesity and T2D.

DOI: https://doi.org/10.1101/2025.11.18.689117