bims-mistre 2026-08-02 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–08–02
thirty-one papers selected by
Ellen Siobhan Mitchell, MitoQ

Novel Endocrine Signaling Axis in Cardiovascular-Kidney-Metabolic Syndrome: Interactions and Therapeutic Potential of FGF21 and GDF15.
GDF15 modulates mitochondrial content and differentiation-associated metabolic remodeling in skeletal muscle cells.
Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.
CCR5/CCL5-Dependent Mitochondrial Dysfunction Contributes to Angiotensin II- Induced Vascular Impairment in Mice.
Mitochondrial Dysfunction in Metabolic-Syndrome-Related MASLD/MASH: Metabolic Mechanisms and Therapeutic Perspectives.
Mitochondrial Dysfunction: From Molecular Mechanisms to Modern Approaches for Basic and Clinical Research.
Hedgehog/GLI Signaling at the Interface of Sterol Metabolism, Mitochondrial ROS Signaling and Cellular Plasticity.
Circulating GDF15 levels reflect metabolic and inflammatory burden in early dysglycemia: findings from the ADIOS cohort.
Astaxanthin as a potential therapeutic agent in polycystic ovary syndrome: a review of its antioxidant, anti-inflammatory, and metabolic mechanisms.
Mitochondrial Dysfunction in Circulating Blood Cells and Biological Aging: A Review of Mechanisms and Evidence.
Effect of Ubiquinol on Cognitive Function, Blood Pressure, Arterial Stiffness, and Biomarkers of Oxidative Stress and Inflammation in the Elderly: A Randomized Trial.
The nuanced role of mitochondrial ROS in modulating aging and aging hallmarks.
Mitochondrial accumulation and lysosomal dysfunction result in mitochondrial plaques in Alzheimer's disease.
Mitochondrial Quality Control in Age-Related Diseases: From Molecular Architecture to Precision Therapeutics.
Dietary Creatine: An Overlooked Variable in Cognitive Aging Resilience?
Escitalopram and N-acetylcysteine alleviate major depressive disorder with cognitive impairment through YTHDC1/ATF4/CHOP-mediated pyroptosis.
VBIT-4 attenuates diabetes-associated cardiovascular mitochondrial dysfunction and ROS production in a mouse model of diabetes and hyperlipidemic cellular assays.
Microglial immunometabolic reprogramming in Alzheimer's disease: From mitochondrial dysfunction and redox imbalance to NLRP3 inflammasome-driven neuroinflammation.
Targeting the Microbiota-Butyrate-BHB Axis As a Potential Metabolic Therapeutic Strategy for Alzheimer's Disease.
Enhanced memory function and reduced perceived stress in older adults with self-reported memory complaints following strawberry leaf extract supplementation: a randomized, double-blind, placebo-controlled study.
Exercise-induced mitochondrial remodeling in energy-demanding organs during aging.
Microglial Mitochondrial Dysfunction: The Storm Center of Post-Stroke Neuroinflammation.
Targeting Reduced Glutathione (GSH) to Promote Metabolic Health: Insights on the Role of Bioactive-Rich Foods and Fasting Protocols.
Sex Hormones and Menopause Hormone Therapy Predict Muscle Strength Across the Lifespan.
A combined stimulus of acute fasting and exercise modulates hippocampal mitochondrial quality control in healthy mice.
Is Ergothioneine an Important Source of Plasma Trimethylamine N-Oxide in Humans?
Epigenetic aging biomarkers in dietary geroscience: feasibility, participant perceptions, and trial design considerations.
Energy paradox in REM sleep: balancing supply and consumption in brain metabolism.
SIRT3 inhibition promotes age-associated vascular impairment by mediating mitochondrial dysfunction and endothelial-to-mesenchymal transition.
Harnessing Brain Age-Specific Effects on the Associations Between Sleep Quality, Glymphatic Function, and Cognition in Normal Ageing Adults: Insights for Gerotherapeutics.
Rutin rescues oocyte developmental competence in primary ovarian insufficiency by restoring mitophagy and suppressing pyroptosis.

J Cell Biochem. 2026 Aug;127(8): e70113

Novel Endocrine Signaling Axis in Cardiovascular-Kidney-Metabolic Syndrome: Interactions and Therapeutic Potential of FGF21 and GDF15.

Changlong Yang, Lei Chen, Hong Xiao, Wanghang Wei, Jiafei Liang, Tao Chen, Tao Yang, Yi Ma.

  Cardiovascular-Kidney-Metabolic Syndrome (CKM) is a multisystem disorder characterized by interdependent cardiovascular, renal, and metabolic dysfunction. It commonly involves metabolic conditions such as type 2 diabetes and obesity and is associated with substantial morbidity and mortality Recently, stress-induced hormone-like cytokines, fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), are emerging as the central two-controllers of the pathophysiological network of CKM. This review is a systemic summary of the biological functions and mechanism of interaction between FGF21 and GDF15 in CKM with a focus on the functions of these two hormones in regulating energy metabolism, insulin sensitivity, inflammation, fibrosis, and cardiovascular protection. We examine their clinical relevance as disease biomarkers and discuss their prospective potential as newer therapeutic targets, in addition to discussing the obstacles that are still in the way of our translations of these findings into therapeutic application. This article will elucidate shared and distinct actions of FGF21 and GDF15 and thereby offer a thorough comprehension of integrative endocrine signaling axis output, as well as its implication to further the development of CKM management.

Keywords:  Cardiovascular‐Kidney‐Metabolic Syndrome; fibroblast growth factor 21; growth differentiation factor 15; metabolic regulation; organ protection; therapeutic targets

DOI:  https://doi.org/10.1002/jcb.70113
Am J Physiol Endocrinol Metab. 2026 Jul 30.

GDF15 modulates mitochondrial content and differentiation-associated metabolic remodeling in skeletal muscle cells.

Bianca Cristine Favero-Santos, Carolina Martins Lazaro, Jung Tae Kim, Dimitrius Santiago P S F Guimarães, Ninon M Flores Barrios, Letícia Basso Gomes, Priscila R Raimundo, Francisco Breno S Teofilo, Michelle Gomes da Silva, Thais Amanda Reia, André Gustavo de Oliveira, Marieli Mariano Gonçalves Dias, André Schwambach Vieira, Ana Carolina Migliorini Figueira, Minho Shong, Leonardo R Silveira.

  Growth differentiation factor 15 (GDF15) is a distant member of the transforming growth factor-β (TGF-β) superfamily increasingly implicated in metabolic regulation. Evidence points to GDF15 as a myokine that regulates systemic energy homeostasis, yet its role in skeletal muscle remains unclear. Here, we investigated whether GDF15 modulates mitochondrial phenotype during myogenesis using mouse C2C12 myoblasts and complementary models. Bioinformatic analyses of GDF15 interaction networks and gene ontology terms revealed enrichment for pathways related to cell differentiation and metabolic regulation. During myogenic differentiation, GDF15 expression increased at both mRNA and protein levels, with cytoplasmic localization and secretion into the extracellular medium, paralleling enhanced mitochondrial content, mitochondrial DNA copy number, and oxygen consumption. Knockdown of GDF15 reduced mitochondrial markers, increased lactate production, and promoted apoptosis, whereas GDF15 overexpression produced opposite effects. Mechanistically, GDF15 overexpression enhanced peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) transactivation and peroxisome proliferator-activated receptor (PPAR) response element activity, effects that were abolished by silencing PPARδ or estrogen-related receptor alpha (ERRα), suggesting a PGC1α-dependent mechanism. Transcriptomic profiling further supported enrichment of nuclear receptor-related pathways, including PPAR and cAMP response element-binding protein (CREB1) signaling. Finally, exercise training in male C57BL/6 mice elevated GDF15 levels in soleus muscle and improved aerobic performance. Together, these findings demonstrate that GDF15 promotes an oxidative phenotype in skeletal muscle cells through PGC1α-dependent activation of PPAR and ERRα, identifying GDF15 as an autocrine regulator of mitochondrial metabolism and muscle adaptation.

Keywords:  Growth differentiation factor 15; Mitochondrial Biogenesis; Myotubes; Skeletal muscle; Transcriptional activation

DOI:  https://doi.org/10.1152/ajpendo.00438.2025
Res Sq. 2026 Jul 22. pii: rs.3.rs-10117408. [Epub ahead of print]

Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.

Michel Thiebaut de Schotten, Cynthia Liu, Catherine Kelly, Ke Bo, Tor Wager, Eugene Mosharov, Martin Picard.

Mitochondria power brain function and cognition, yet no label-free, non-invasive method has existed to explore their relationship to ageing, disease, and cognition in humans. The MitoBrainMap framework predicts mitochondrial features from magnetic resonance data alone, potentially bridging cellular biology with macroscale brain organization. Here we tested whether it captures meaningful age- and disease-related variation across individuals. MR-predicted mitochondrial density and tissue respiratory capacity declined with age, whereas intrinsic mitochondrial respiratory capacity was relatively preserved. Correlations among predicted features matched known mitochondrial biology, supporting preliminary construct validity. In patients with genetically confirmed mitochondrial diseases, predicted maps revealed region-specific alterations, notably the expected compensatory upregulation of nuclear- encoded complex II. Predicted features were further associated with the energetic stress marker GDF15 and with cognitive performance, linking brain mitochondrial estimates to systemic physiology and behavior. These findings introduce a first-generation, label-free neuroimaging-based mitochondrial mapping as a non-invasive window into living human brain mitochondria.

DOI: https://doi.org/10.21203/rs.3.rs-10117408/v1
bioRxiv. 2026 Jul 22. pii: 2026.03.10.710946. [Epub ahead of print]

CCR5/CCL5-Dependent Mitochondrial Dysfunction Contributes to Angiotensin II- Induced Vascular Impairment in Mice.

Gustavo Felix Pimenta, Ariane Bruder, Tyler Beling, Sergio Guerrero, Luis Oliveira de Moraes, Carlos Renato Tirapelli, Thiago Bruder-Nascimento.

AIM: Chemokine signaling contributes to vascular inflammation and dysfunction in hypertension, yet the intracellular mechanisms linking CCL5/CCR5 activation to vascular impairment remain unclear. We tested the hypothesis that angiotensin II (Ang II) amplifies CCL5/CCR5 signaling to promote mitochondrial dysfunction and oxidative stress in the vasculature.
METHODS: Wild-type and CCR5-deficient mice were infused with Ang II for 14 days, and separate cohorts received recombinant CCL5. Vascular function and remodeling were assessed in aorta and mesenteric arteries, while mitochondrial respiration, membrane potential, and reactive oxygen species (ROS) production were evaluated in vascular smooth muscle cells (VSMCs).
RESULTS: Ang II increased circulating CCL5 levels and upregulated vascular CCR5 expression. CCR5 deficiency protected against Ang II-induced vascular dysfunction, remodeling, and inflammation. CCL5 infusion impaired endothelium-dependent relaxation and enhanced contractility without inducing structural remodeling. In VSMCs, CCL5 disrupted mitochondrial respiration, reduced maximal respiratory capacity, altered membrane potential, and increased mitochondrial ROS in a CCR5-dependent manner. Mitochondrial antioxidant treatment restored endothelial function but did not normalize enhanced contractility. In addition, vessels from CCL5-treated mice were unresponsive to acute mitochondrial uncoupling, consistent with impaired mitochondrial bioenergetic reserve.
CONCLUSION: Ang II amplifies CCL5/CCR5 signaling to drive mitochondrial dysfunction and oxidative stress, thereby promoting vascular impairment, and identify this pathway as a potential therapeutic target in hypertension.

DOI: https://doi.org/10.64898/2026.03.10.710946
Metabolites. 2026 Jul 11. pii: 489. [Epub ahead of print]16(7):

Mitochondrial Dysfunction in Metabolic-Syndrome-Related MASLD/MASH: Metabolic Mechanisms and Therapeutic Perspectives.

Jin Jin, Yang Cheng.

   BACKGROUND/OBJECTIVES: Metabolic-dysfunction-associated steatotic liver disease (MASLD) and metabolic-dysfunction-associated steatohepatitis (MASH) arise in the setting of obesity, insulin resistance, type 2 diabetes, and metabolic syndrome. This review examines how mitochondrial dysfunction participates in the transition from lipid accumulation to hepatocyte injury, inflammation, and fibrosis, and how evidence from human, animal, and in vitro studies should be interpreted.
METHODS: We provide a narrative synthesis of mechanistic, translational, and clinical studies on hepatic mitochondrial metabolism, fatty acid oxidation, oxidative phosphorylation, redox stress, organelle crosstalk, mitophagy, mitochondrial biogenesis and proteostasis, mitochondrial danger signals, the gut-liver-mitochondria axis, and mitochondria-related therapeutic strategies.
RESULTS: In early metabolic overload, mitochondrial oxidation may increase as an adaptive response. With persistent substrate pressure, this adaptation can become inefficient, with impaired fatty acid disposal, less efficient oxidative phosphorylation, reactive oxygen species production, redox imbalance, defective mitochondrial quality control, altered mitochondrial biogenesis, mitochondrial unfolded protein response (UPRmt)-related proteostatic stress and mtDNA instability. Mitochondrial DNA and RNA released from damaged organelles may also activate cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), inflammasome, and RNA-sensing pathways, linking hepatocyte stress to macrophage activation, stellate cell activation, extracellular matrix deposition, and fibrosis.
CONCLUSIONS: The current evidence supports mitochondria as a stage-dependent amplifier of metabolic liver injury rather than a uniform initiating event. Clinically, the strongest evidence remains with upstream metabolic unloading and liver-directed metabolic therapy, whereas direct mitochondrial restoration and quality-control targeting remain promising but less mature.

Keywords:  MASH; MASLD; fibrosis; insulin resistance; metabolic syndrome; metabolomics; mitochondrial dysfunction; mitochondrial quality control; mitophagy; oxidative stress

DOI:  https://doi.org/10.3390/metabo16070489
Biomedicines. 2026 Jul 07. pii: 1521. [Epub ahead of print]14(7):

Mitochondrial Dysfunction: From Molecular Mechanisms to Modern Approaches for Basic and Clinical Research.

Tatiana V Kirichenko, Yaroslav D Tolkachev, Stepan M Bessonov, Alexander M Markin, Yuliya V Markina.

  Mitochondria play a vital role in fundamental cellular processes, serving as key regulators of energy metabolism, apoptosis, oxidative stress, calcium homeostasis. Mitochondrial dysfunction is widely regarded as a common pathogenic pathway in the development of widespread chronic diseases, such as metabolic disorders, cardiovascular disease, neurodegeneration, and malignancies. Modern research examines mitochondrial dynamics, mitophagy, mitochondrial biogenesis, mtDNA damage, and the role of reactive oxygen species not only for in-depth understanding of disease pathogenesis but also for identifying diagnostic markers and therapeutic targets. Determining mitochondrial dysfunction is a significant challenge and should involve a comprehensive approach with reliable assessment methods that take into account the dynamic state, number, and localization of mitochondria. The review summarizes the results of the studies exploring the pathogenetic role of mitochondrial dysfunction in the development of widespread chronic diseases and current methods of its evaluation for the integration of mitochondrial dysfunction biomarkers into modern diagnostic strategies and development of mitochondria-target treatment approaches.

Keywords:  cardiovascular disease; flow cytometry; metabolic syndrome; mitochondrial dysfunction; mtDNA; neurodegenerative diseases; oncology; seahorse assay; transcriptome analysis

DOI:  https://doi.org/10.3390/biomedicines14071521
Antioxidants (Basel). 2026 Jul 21. pii: 905. [Epub ahead of print]15(7):

Hedgehog/GLI Signaling at the Interface of Sterol Metabolism, Mitochondrial ROS Signaling and Cellular Plasticity.

Nicolas Jullien, Sabine François.

  Classically, Hedgehog (Hh)/GLI signaling is recognized as a developmental pathway. Increasing evidence indicates that it also contributes to cellular metabolism and adaptation to stress. In this review, we examine the involvement of Hh/GLI signaling in mitochondrial function and redox homeostasis. Mitochondria are major sources of reactive oxygen species (ROS), which act as signaling molecules in cellular adaptation. Hh signaling both influences and responds to ROS production: GLI activity is regulated by redox-dependent mechanisms, and Hh signaling is associated with mitochondrial bioenergetics, dynamics and quality-control pathways. These interactions may contribute to metabolic adaptation in physiological and pathological settings. We also discuss the contribution of sterol metabolism to this regulatory network. Cholesterol and oxysterols modulate Smoothened activation, linking lipid metabolism to mitochondrial function and redox balance. NRF2-dependent antioxidant pathways maintain mitochondrial redox homeostasis, although direct mechanistic crosstalk with Hh/GLI signaling remains incompletely defined. At the tissue level, Hh signaling is involved in responses to irradiation, inflammation, fibrosis, aging and regeneration. Depending on the biological context, pathway activation may support adaptive responses or contribute to tissue dysfunction. Overall, current evidence supports a role for Hh/GLI signaling in mitochondrial redox adaptation through the integration of metabolic and oxidative signals.

Keywords:  GLI transcription factors; NRF2; cellular plasticity; hedgehog signaling; mitochondria; reactive oxygen species; redox homeostasis; sterol metabolism

DOI:  https://doi.org/10.3390/antiox15070905
Diabetes Res Clin Pract. 2026 Jul 27. pii: S0168-8227(26)00381-5. [Epub ahead of print]239 113461

Circulating GDF15 levels reflect metabolic and inflammatory burden in early dysglycemia: findings from the ADIOS cohort.

Ji Yoon Kim, Ah Hyeon Lee, Jiyoon Lee, Hye-Min Jang, Sin Gon Kim, Dong-Hoon Kim, Nam Hoon Kim.

   AIMS: To investigate whether circulating growth differentiation factor 15 (GDF15) measured at diagnosis reflects the overall metabolic burden in early dysglycemia.
METHODS: Baseline data from the prospective Anam Diabetes Observational Study were analyzed in 281 treatment-naive adults with normal glucose tolerance (NGT), prediabetes, or newly diagnosed type 2 diabetes. Participants with early dysglycemia were categorized into tertiles of circulating GDF15 levels. Correlation and multivariable logistic regression analyses evaluated associations between GDF15 levels and predefined metabolic abnormalities.
RESULTS: The circulating levels of GDF15 increased progressively from NGT to prediabetes and newly diagnosed type 2 diabetes. Among individuals with early dysglycemia, the highest GDF15 tertile was independently associated with increased odds of central obesity (adjusted OR: 2.59, 95% CI: 1.19-5.63) and elevated HOMA2-IR (adjusted OR: 4.12, 95% CI: 1.70-9.99), high-sensitivity C-reactive protein (adjusted OR: 2.69, 95% CI: 1.22-5.92), and fatty liver index (adjusted OR: 2.75, 95% CI: 1.22-6.18). The prevalence of multiple metabolic abnormalities increased stepwise across the GDF15 tertiles.
CONCLUSIONS: Circulating levels of GDF15 measured at diagnosis reflect the burden of adverse metabolic and inflammatory traits in individuals with early dysglycemia, and may serve as an integrated indicator of metabolic health early in the disease course.

Keywords:  Early dysglycemia; Growth differentiation factor 15; Insulin resistance; Metabolic heterogeneity; Type 2 diabetes mellitus

DOI:  https://doi.org/10.1016/j.diabres.2026.113461
Front Reprod Health. 2026 ;8 1901207

Astaxanthin as a potential therapeutic agent in polycystic ovary syndrome: a review of its antioxidant, anti-inflammatory, and metabolic mechanisms.

Jialai Wang, Ying Yang, Ziwei Wang, Chengdong Liu, Yanhua Han, Xiaoke Wu, Hui Chang.

  Polycystic ovary syndrome (PCOS) is the most common heterogeneous disorder among women of reproductive age, characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphological changes as its core clinical features. This disease severely affects women's reproductive health and significantly increases the risk of metabolic complications. The pathogenesis of PCOS is complex, involving various pathophysiological mechanisms such as oxidative stress, chronic low-grade inflammation, and insulin resistance. Currently, lifestyle interventions and first-line pharmacological treatments are the primary clinical strategies for managing PCOS. However, existing approaches face numerous limitations in terms of efficacy, safety, and patient compliance, including incomplete therapeutic effects, drug-related side effects, poor adherence, and a lack of long-term safety data, which necessitate further optimization and breakthroughs. Natural compounds have been widely utilized as therapeutic agents worldwide, with some showing potential advantages in preclinical and pharmacological studies, positioning them as potential alternatives to modern drugs. In recent years, astaxanthin, a natural compound, has garnered attention for its auxiliary effects in the treatment of PCOS due to its potent antioxidant and anti-inflammatory properties. Astaxanthin, a strong natural antioxidant derived from Haematococcus pluvialis, exhibits significant antioxidant, anti-inflammatory, anti-proliferative, and anti-apoptotic activities. To systematically evaluate the therapeutic potential of astaxanthin for PCOS, this study conducted a systematic review in strict accordance with the PICOS principles. A comprehensive literature search was performed across PubMed, Web of Science, and Scopus for relevant studies published between January 2020 and March 2026. The retrieved records were screened based on predefined inclusion and exclusion criteria, and the finally included studies were subjected to mechanistic analysis. This review provides a comprehensive analysis of the potential mechanisms by which astaxanthin, as a dietary supplement, improves PCOS through various pathways, including enhancing insulin sensitivity, activating the Nrf2 antioxidant pathway, inhibiting the NF-κB inflammatory signaling pathway, and modulating cellular apoptosis. Furthermore, it delineates the limitations and therapeutic prospects of astaxanthin supplementation, clarifying its significant value in the adjuvant treatment of PCOS and highlighting the key issues that warrant further investigation.

Keywords:  anti-apoptotic; anti-inflammatory; antioxidative stress; astaxanthin; polycystic ovary syndrome

DOI:  https://doi.org/10.3389/frph.2026.1901207
Biomolecules. 2026 Jul 01. pii: 972. [Epub ahead of print]16(7):

Mitochondrial Dysfunction in Circulating Blood Cells and Biological Aging: A Review of Mechanisms and Evidence.

Abdullah M AlShahrani, S Rehan Ahmad.

  Chronological age tells us how long a person has lived-but not how well. Two individuals of the same age can differ dramatically in their cellular health, disease risk, and functional capacity. This gap between calendar age and biological age has driven growing interest in biomarkers that reflect true cellular aging rather than years lived. Mitochondria sit at the heart of this problem. Far more than cellular power plants, these organelles govern energy production, oxidative stress, immune signaling, and programmed cell death. As the body ages, mitochondria deteriorate in consistent and measurable ways-and crucially, these changes can be detected in circulating blood cells, offering a minimally invasive window into the body's biological age. This narrative review synthesizes two decades of research (2005-2025) on three blood-based mitochondrial markers: mitochondrial DNA copy number (mtDNA-CN) in peripheral blood mononuclear cells, mitochondrial membrane potential (MMP), and cell-free mitochondrial DNA (cf-mtDNA) in plasma. Across 68 carefully selected studies, we evaluate the strength, consistency, and clinical relevance of each marker, alongside their associations with cardiovascular disease, metabolic dysfunction, cognitive decline, and mortality. The evidence is promising but still maturing. Significant methodological variation across studies limits direct comparisons, and robust prospective outcome data remain limited. We propose a four-phase framework for responsible clinical translation and identify specific research investments needed-from measurement standardization to large cohort studies and intervention trials-before these markers can responsibly inform patient care.

Keywords:  aging biomarkers; biological aging; cell-free mitochondrial DNA; clinical translation; inflammaging; mitochondrial dysfunction; mitochondrial membrane potential; mtDNA copy number; oxidative stress; peripheral blood mononuclear cells

DOI:  https://doi.org/10.3390/biom16070972
Antioxidants (Basel). 2026 Jun 27. pii: 806. [Epub ahead of print]15(7):

Effect of Ubiquinol on Cognitive Function, Blood Pressure, Arterial Stiffness, and Biomarkers of Oxidative Stress and Inflammation in the Elderly: A Randomized Trial.

Madeleine C Nankivell, Franklin Rosenfeldt, Jeffery M Reddan, Judy B de Haan, Cherry Zhang Ping, Beaudan Campbell-Brown, Andrew Pipingas, Matthew P Pase, Ruchong Ou, Matthew B Cooke, David L Hare, Con Stough.

  Older age is typically characterized by decrements in cognitive performance relative to younger adults, though it may not necessarily reach clinical impairment. Dietary supplementation with ubiquinol, the reduced form of the antioxidant and cellular energizer CoQ10, may support cognitive function in older individuals. In the current randomized clinical trial of 111 adults aged 60 years and older (ubiquinol, n = 61; placebo, n = 50), 90 days of ubiquinol (200 mg) supplementation resulted in plasma CoQ10 levels being four times that of the placebo group at study end (p < 0.001). We found that ubiquinol supplementation did not facilitate group differences (controlling for baseline values and relevant demographics) in cognitive function, blood biomarkers reflective of oxidative stress or inflammation, measures of cardiovascular health, or subjective mood at study end. However, regression analyses revealed a positive association between change in plasma CoQ10 and memory performance, as well as a negative association between change in oxidative stress and memory performance at study end in those who received ubiquinol but not placebo. We conclude that adequately powered future clinical trials should examine whether long-term supplementation with ubiquinol can support cognitive function in older adults at risk of cognitive decline or with health conditions predisposing them to risk factors associated with decline.

Keywords:  CoQ10; aging; cardiovascular; cognition; inflammation; oxidative stress; ubiquinol

DOI:  https://doi.org/10.3390/antiox15070806
Redox Biol. 2026 Jul 24. pii: S2213-2317(26)00318-6. [Epub ahead of print]96 104319

The nuanced role of mitochondrial ROS in modulating aging and aging hallmarks.

Annika Müller-Eigner, Elena Morin, Katherine S Morton, Andrew P Wojtovich.

  Aging is characterized by a progressive decline in cellular integrity and function, making it a major risk factor for numerous disease pathologies. Mitochondrial dysfunction and oxidative stress have long been recognized as contributors to the aging phenotype. The loss of mitochondrial function and the overproduction of reactive oxygen species (ROS) are linked to many hallmarks of aging and are associated with a wide range of diseases; however, their role in the aging process is nuanced. Mitochondria produce ROS as harmful respiratory byproducts, but ROS can also act as a signaling molecule with emerging functions linked to variables such as location, timing, and quantity. Similarly, mitochondrial dysfunction is often broadly categorized, overlooking its multifaceted nature and diverse contributions to aging. Due to this complexity, our understanding of how mitochondrial ROS production shapes disease processes and aging hallmarks remains limited. This review aims to clarify the complex and nuanced role of mitochondrial ROS in aging by focusing on ROS production within mitochondria, especially complexes I, II and III, and exploring how these localized ROS influence various hallmarks of aging to contribute to the aging phenotype.

Keywords:  Aging; And complex III; Complex I; Complex II; Hallmarks of aging; Mitochondria; Mitochondrial ROS; Oxidative stress

DOI:  https://doi.org/10.1016/j.redox.2026.104319
Nat Neurosci. 2026 Jul 29.

Mitochondrial accumulation and lysosomal dysfunction result in mitochondrial plaques in Alzheimer's disease.

Xiuli Dan, Deborah L Croteau, Wenlong Liu, Xixia Chu, Ross A McDevitt, Paul D Robbins, Vilhelm A Bohr.

Dysfunctional mitophagy is proposed as a key component of Alzheimer's disease (AD) pathology, yet direct in vivo evidence and mechanistic insights are still lacking. Here we show that AD model mice expressing a mitophagy reporter (APP/PSEN1/mt-Keima) develop large accumulation of acidic and neutral mitochondria within neuronal processes that form a previously unrecognized pathological structure termed mitochondrial plaques (MPs). The development of MPs is driven by abnormal mitochondrial buildup and lysosomal recruitment occurs as a delayed response to promote mitochondrial degradation. However, degradation through mitophagy is incomplete due to impaired lysosomal functions, resulting in accumulation of both neutral and acidic mitochondria. MPs frequently codevelop with amyloid to form mixed plaques but can also emerge independently at early stages of disease. Notably, MPs were also identified in the 5xFAD AD mouse model and postmortem human AD brains. These findings establish MPs as a new pathological entity in AD.

DOI: https://doi.org/10.1038/s41593-026-02390-1
Antioxidants (Basel). 2026 Jun 30. pii: 830. [Epub ahead of print]15(7):

Mitochondrial Quality Control in Age-Related Diseases: From Molecular Architecture to Precision Therapeutics.

Jingmin Che, Ye Sun, Fang Wang, Qing Feng, Cuixiang Xu, Xuhui Li.

   BACKGROUND: Mitochondria are the primary organelles that regulate cellular bioenergetic metabolism and maintain homeostasis, providing essential structural support for optimal cell survival. Nonetheless, advancing age leads to cumulative damage to mitochondrial structure and functional integrity, which is a defining characteristic of biological aging and is closely linked to the emergence and progression of numerous age-related diseases, including neurodegenerative disorders, cardiovascular diseases, and metabolic disorders.
SCOPE OF REVIEW: This article offers a thorough summary and review of mitochondrial quality control (MQC), emphasizing numerous critical processes, including mitochondrial biosynthesis, dynamic remodeling (fusion and fission), and mitophagy. We thoroughly elucidate the molecular pathways that regulate MQC and demonstrate how age-related dysregulation precipitates cellular senescence, highlighting the transition from physiological maintenance to pathological malfunction, which ultimately culminates in cellular aging.
CONCLUSIONS AND IMPLICATIONS: This study systematically elaborates the pathophysiological mechanisms in the field, comprehensively evaluates the clinical translational potential of targeting the MQC pathway, highlights the key objectives of "restoring mitochondrial plasticity and removing dysfunctional mitochondria", and explores novel intervention strategies. The restoration of normal mitochondrial function in cells throughout aging is a very promising path for precision medicine therapeutics with great translational potential, according to recent state-of-the-art research. The development of novel therapeutic approaches to improve functional healthy mitochondria can effectively delay aging and reduce the rising global burden of age-related diseases.

Keywords:  age-related diseases; cellular senescence; metabolic homeostasis; mitochondrial quality control; mitophagy; therapeutic targets

DOI:  https://doi.org/10.3390/antiox15070830
Geriatr Gerontol Int. 2026 Aug;26(8): e70732

Dietary Creatine: An Overlooked Variable in Cognitive Aging Resilience?

Marco Machado.

Dietary creatine is an underexplored factor in cognitive aging resilience. Evidence links higher intake to improved cognitive performance, yet many older adults consume suboptimal levels. This perspective advocates for improved assessment tools and rigorous trials to clarify creatine's role in brain health.

DOI: https://doi.org/10.1111/ggi.70732
Behav Brain Res. 2026 Jul 27. pii: S0166-4328(26)00379-7. [Epub ahead of print] 116403

Escitalopram and N-acetylcysteine alleviate major depressive disorder with cognitive impairment through YTHDC1/ATF4/CHOP-mediated pyroptosis.

Yuting Zhou, Yuqian Zhang, Lixia Yang.

   BACKGROUND: Cognitive impairment (CI) is an important factor contributing to poor prognosis in major depressive disorder (MDD). Endoplasmic reticulum stress and microglial inflammatory response are closely associated with the occurrence and development of MDD with CI. Escitalopram (ESC) and N-acetylcysteine (NAC) are two drugs used to improve depression. However, the therapeutic efficacy and underlying molecular mechanisms of ESC and NAC in treating MDD with CI are still not fully understood.
METHODS: The depression rat was established using the chronic unpredictable mild stress (CUMS) protocol. The antidepressant effects of ESC and NAC were evaluated through behavioral tests including the open field test, sucrose preference test, and Morris water maze test and. The underlying molecular mechanisms were investigated using ELISA and immunofluorescence techniques.
RESULTS: The CUMS group of rats showed decreased responsiveness and memory capacity, which were significantly improved following intervention with ESC and NAC. Treatment with ESC and NAC alleviated hippocampal injury in the CUMS group of rats. The expression of microglial activation markers CD68 and IBA1 in hippocampal tissue was significantly reduced. The levels of NLRP3 inflammasome and pro-inflammatory cytokines IL-6, IL-18, and IL-1β in the hippocampus were significantly decreased. Mechanistically, ESC and NAC downregulate ATF4/CHOP expression by inhibiting the m6A reader YTHDC1, thereby reducing hippocampal cell pyroptosis.
CONCLUSION: This study demonstrates that ESC and NAC alleviate hippocampal tissue damage by modulating YTHDC1/ATF4/CHOP-mediated pyroptosis, thereby improving MDD with CI. These findings provide experimental evidence supporting the therapeutic potential of targeting YTHDC1/ATF4/CHOP-mediated pyroptosis in MDD-associated CI.

Keywords:  Escitalopram; N-acetylcysteine; apoptosis; endoplasmic reticulum stress; major depressive disorder

DOI:  https://doi.org/10.1016/j.bbr.2026.116403
Free Radic Biol Med. 2026 Jul 29. pii: S0891-5849(26)00976-7. [Epub ahead of print]255 393-405

VBIT-4 attenuates diabetes-associated cardiovascular mitochondrial dysfunction and ROS production in a mouse model of diabetes and hyperlipidemic cellular assays.

Konstantin N Belosludtsev, Anna I Ilzorkina, Dmitriy A Khurtin, Irina B Mikheeva, Mikhail V Dubinin, Dmitriy A Serov, Eugeny Yu Talanov, Lyudmila A Matveeva, Alexander V Chulkov, Maxim N Karagyaur, Natalia N Belosludtseva, Jiankang Liu.

Mitochondrial dysfunction and oxidative stress are primary cellular factors in the development of diabetes mellitus and its associated cardiovascular complications. Targeting these processes represents a potential therapeutic strategy. Voltage-dependent anion channels (VDAC) of the mitochondrial outer membrane, which regulate metabolite transport between mitochondria and the cytosol, have emerged as candidate targets for diabetes intervention. In this work, we studied the effect of VBIT-4, an inhibitor of VDAC oligomerization, on the development of mitochondrial dysfunction in cardiovascular cells in a model of diabetes mellitus in vivo and in vitro. The metabolic and cardiac effects of VBIT-4 (10 mg/kg every 48 h for 21 days, intraperitoneally) were assessed in a mouse model of high-fat diet/streptozotocin-induced diabetes. Administration of VBIT-4 was associated with lower blood glucose levels and partial normalization of HR and QT intervals in diabetic animals. Analysis of mitochondrial TEM micrographs and cardiac mitochondrial functional activity indicated that VBIT-4 partially improved State 3 respiration and significantly reduced TBARS production in heart mitochondria of diabetic animals. In cell culture models (primary mouse pulmonary vascular endothelium and HEK293T cells) under hyperlipidemic conditions, both VBIT-4 treatment and silencing of VDAC1 expression significantly reduced DCF and MitoSOX fluorescence, suggesting a potential decrease in mitochondrial reactive oxygen species overproduction. Molecular docking and dynamics simulations predicted that VBIT-4 interacts with the α-helical N-terminus of VDAC1, potentially stabilizing it within the channel pore. Together, these findings suggest that the cardioprotective effects of VBIT-4 in the diabetic setting may involve suppression of VDAC1 oligomerization and associated mitochondrial ROS overproduction.

DOI: https://doi.org/10.1016/j.freeradbiomed.2026.07.049
J Alzheimers Dis. 2026 Jul 31. 13872877261469862

Microglial immunometabolic reprogramming in Alzheimer's disease: From mitochondrial dysfunction and redox imbalance to NLRP3 inflammasome-driven neuroinflammation.

Siyu Li, Juntao Jin, Yingying Liu, Jing Yuan, Yuhan Dong, Ziyi Wang, Lu Li, Yamin Zhang.

  Alzheimer's disease (AD) is increasingly recognized as a disorder in which amyloid-β deposition and tau pathology interact with neuroinflammation and metabolic dysregulation. Although mitochondrial dysfunction, redox imbalance, and NLRP3 inflammasome activation have each been implicated in AD pathogenesis, their mechanistic continuity within microglial immunometabolic reprogramming remains insufficiently defined. This narrative review integrates mechanistic, preclinical, and human-relevant evidence to propose a stage-dependent mitochondrial dysfunction-redox imbalance-NLRP3 inflammasome axis. We discuss how AD-related stimuli shift microglia toward a pro-inflammatory metabolic phenotype; how impaired mitochondrial quality control promotes reactive oxygen species generation and oxidized mitochondrial DNA release; and how these signals facilitate NLRP3 inflammasome activation and sustained inflammatory amplification. We further summarize therapeutic strategies targeting upstream mitochondrial homeostasis, intermediate metabolic-redox coupling, and downstream NLRP3 signaling, while emphasizing the translational limitations and biomarker needs. We conclude that this proposed axis provides a testable stage-dependent framework for interpreting chronic, self-amplifying neuroinflammation in AD and may inform biomarker-guided, combinatorial therapeutic strategies.

Keywords:  Alzheimer's disease; NLRP3 inflammasome; immunometabolic reprogramming; microglia; mitochondrial dysfunction; neuroinflammation; redox imbalance

DOI:  https://doi.org/10.1177/13872877261469862
Aging Dis. 2026 Jul 22.

Targeting the Microbiota-Butyrate-BHB Axis As a Potential Metabolic Therapeutic Strategy for Alzheimer's Disease.

Vijay Kumar, Sinae Jang, Yebeen Choi, Sujin Kim, Yunkwon Nam, MyeongHeon You, Minho Moon.

Alzheimer's disease (AD) is increasingly linked to metabolic and microbial dysregulations, with butyrate and β-hydroxybutyrate (BHB) identified as key modulators. BHB is a ketone body primarily produced by the liver during periods of low glucose availability, and BHB levels are reduced in the AD brain and peripheral blood. Butyrate, a microbiota-derived short-chain fatty acid, is also reduced in the peripheral blood in association with gut microbiota dysbiosis. The reduction of butyrate and BHB, together with gut microbiota dysbiosis, is commonly observed in AD patients and correlates with cognitive decline and AD-related pathologies. Reduced levels of butyrate and BHB may impair energy metabolism, exacerbating amyloid-beta (Aβ) and tau pathologies. In contrast, preliminary evidence from interventional and ketogenic studies suggests that increasing butyrate and BHB levels may attenuate AD-related pathologies, such as Aβ and tau abnormalities, while improving cognitive function. Emerging evidence suggests that both butyrate and BHB can cross the blood-brain barrier (BBB), suppressing oxidative stress and pro-inflammatory cytokines and potentially mitigating Aβ aggregation and tau hyperphosphorylation. Accordingly, therapeutic strategies targeting the microbiota-butyrate-BHB axis represent a promising and biologically plausible approach that warrants further rigorous clinical investigation for the prevention and treatment of AD. This review comprehensively examines the roles of butyrate and BHB in ameliorating key AD-related pathologies, including Aβ aggregation, tau hyperphosphorylation, neuroinflammation, and neurodegeneration. Additionally, the review explores the bidirectional association between butyrate/BHB and gut dysbiosis in AD, including how dysbiosis reduces butyrate/BHB levels while elevating them may reverse dysbiosis and improve gut-brain axis function. Collectively, these findings suggest that butyrate and BHB emerge as promising candidates for potential novel adjunctive therapies for AD, although supporting human evidence remains preliminary and heterogeneous.

DOI: https://doi.org/10.14336/AD.2026.0606
J Nutr Health Aging. 2026 Jul 27. pii: S1279-7707(26)00162-4. [Epub ahead of print]30(9): 100929

Enhanced memory function and reduced perceived stress in older adults with self-reported memory complaints following strawberry leaf extract supplementation: a randomized, double-blind, placebo-controlled study.

Valérie Dormal, Stéphanie Dudonné, Christian Gombert, Lise Laurençon, Julien Fouilland, Marine Buchet, Inès Zacharias, Sylvie Copine, Laurent Simar, Louise Deldicque.

   BACKGROUND: Age-related changes in cognitive performance represent a growing concern for older adults. Strawberry leaf extract (SLE), a polyphenol-rich botanical supplement containing ellagitannins, has been suggested to exert neuroprotective effects based on preclinical evidence. However, to date, no human studies have evaluated its potential benefits on cognitive performance.
OBJECTIVES: The present study aimed to evaluate the impact of SLE supplementation on cognitive performance (i.e., memory abilities and executive functions) and mental well-being (stress level, sleep quality and fatigue) in healthy older adults with subjective memory complaints.
METHODS: In this randomized, double-blind, placebo-controlled trial, 109 participants aged 60-80 years were randomly assigned to receive either SLE (300 mg/day) or a matching placebo for 12 weeks. Cognitive performance was assessed at baseline, midpoint, and endpoint using Cambridge Neuropsychological Test Automated Battery (CANTAB) subtests targeting memory abilities and executive functioning. Self-perceived stress level, sleep quality, fatigue, and memory complaints were evaluated using validated questionnaires.
RESULTS: No significant treatment-by-time interactions were observed for the primary or secondary outcomes in the mixed-effects models. Exploratory analyses showed significant within-group improvements in episodic memory in the SLE group, with reductions in PAL total errors at Week 6 (-4.2 ± 10.0; p = 0.001) and Week 12 (-5.5 ± 11.2; p = 0.001). Between-group comparisons of change from baseline showed greater improvements with SLE than placebo for PAL total errors at Week 6 (p = 0.016) and Week 12 (p = 0.048), and for perceived stress at Week 6 (p = 0.043). The product was well tolerated, with no serious adverse events reported.
CONCLUSIONS: Although the primary analysis did not demonstrate significant treatment-by-time interactions, exploratory analysis suggested that SLE may have beneficial effect on episodic memory and self-perceived stress level in healthy older adults with self-reported memory complaints. Further studies are warranted to confirm these effects.

Keywords:  Clinical study; Cognitive performance; Ellagitannins; Memory; Older adults; Strawberry leaf extract; Stress

DOI:  https://doi.org/10.1016/j.jnha.2026.100929
iScience. 2026 Aug 21. 29(8): 116791

Exercise-induced mitochondrial remodeling in energy-demanding organs during aging.

Zhuoyang Zhou, Jianhong Gao, Minghui Wang, Hu Zhang.

Age-associated organ dysfunction markedly impairs quality of life and increases mortality in older adults. Aging frequently results in compromised mitochondrial function in organs with high energy demands, such as skeletal muscle, the brain, heart, kidneys, and liver. This impairment leads to excessive production of reactive oxygen species, increased inflammation, energy deficits, and aberrant cellular signaling, collectively fostering cellular senescence, and chronic diseases. Empirical research has demonstrated that regular physical exercise preserves mitochondrial integrity. This review summarizes common and specific responses to exercise in mitochondrial regulation across various organs and provides a comprehensive cross-organ analysis. The objective was to elucidate the molecular mechanisms through which exercise confers anti-aging effects and mitigates degenerative functional decline by restoring mitochondrial homeostasis. This review provides a theoretical foundation for developing targeted anti-aging interventions and for attenuating aging in multiple organs through lifestyle modifications.

DOI: https://doi.org/10.1016/j.isci.2026.116791
CNS Neurosci Ther. 2026 Jul;32(7): e71060

Microglial Mitochondrial Dysfunction: The Storm Center of Post-Stroke Neuroinflammation.

Ruchong Fan, Chuan Wang, Zi Lin, Shiling Chen, Chao Pan, Hao Nie, Chuan Qin, Xuan Wu, Zhouping Tang.

   BACKGROUND: Stroke remains a major global cause of death and disability, with many patients either missing the therapeutic window or responding poorly to current first-line treatments. Consequently, secondary neurological injury, driven predominantly by neuroinflammation, has emerged as a critical therapeutic target. Microglia rapidly sense post-stroke microenvironmental changes and adopt distinct inflammatory phenotypes that shape pathophysiological outcomes.
RESULTS: Accumulating evidence, including high-resolution spatial profiling and single-cell omics, positions mitochondrial dysfunction at the core of these responses. This review synthesizes recent findings on microglial mitochondrial dysfunction in stroke, introducing the concept of a microglial mitochondrial "storm center". In this model, reactive oxygen species (ROS) trigger an inflammatory cascade, while impairments in mitochondrial quality control (MQC) exacerbate pathogenic signaling. Metabolic reprogramming further sustains inflammatory polarization, influencing interactions with neurons, astrocytes, and endothelial cells.
CONCLUSIONS: This "storm center" provides a conceptual framework for developing strategies to mitigate secondary brain injury. Finally, this review highlights key molecular mechanisms, potential therapeutic targets, and translational opportunities, providing a stronger foundation for future stroke research and therapeutic innovation.

Keywords:  fusion/fission dynamics; metabolic reprogramming; microglia; mitochondrial dysfunction; mitochondrial transplantation; mitophagy; neuroinflammation; stroke

DOI:  https://doi.org/10.1002/cns.71060
Int J Mol Sci. 2026 Jul 18. pii: 6400. [Epub ahead of print]27(14):

Targeting Reduced Glutathione (GSH) to Promote Metabolic Health: Insights on the Role of Bioactive-Rich Foods and Fasting Protocols.

Periklis Vardakas, Zoi Skaperda, Paraskevi Maria Nechalioti, Sotiria Makri, Anastasia Patouna, Maria Gkasdrogka, Thomas Karampatzakis, Kyriaki Kroustalli, Georgios Papageorgiou, Evanthia Angeli, Dimitrios Foulos, Fotios Tekos, Demetrios Kouretas.

  The ever-increasing disparity between lifespan and healthspan represents a challenging global issue, with metabolic dysregulation playing a central role in the initiation and progression of chronic non-communicable diseases (NCDs). This review highlights the importance of maintaining optimal redox homeostasis, with particular emphasis on reduced glutathione (GSH), for preserving metabolic health during aging. GSH participates in several physiological processes, including antioxidant defense, xenobiotic detoxification, redox signaling, and metabolic regulation. Diminished GSH levels are consistently reported in obesity, insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver, and cardiovascular diseases. Current evidence from human clinical studies indicates that foods rich in bioactive constituents can enhance GSH levels and stimulate GSH-dependent enzyme activity, with the Nrf2/Are signaling pathway being a central mechanistic link. Fasting may promote adaptive redox responses by inducing mild oxidative stress and activating the same molecular mechanism, although the effects on GSH-related antioxidant mechanisms remain heterogeneous across fasting protocols and study populations. Altogether, the available clinical evidence suggests that these nutritional and lifestyle interventions exhibit more consistent beneficial effects in individuals characterized by increased oxidative burden and underlying metabolic dysfunction. Interindividual differences in GSH responses further underscore the need for targeted, tailor-made approaches that account for genetic, epigenetic, and lifestyle factors. Collectively, targeting GSH homeostasis through nutritional and lifestyle interventions represents a promising strategy for improving metabolic health and may further contribute to healthy aging, positioning redox biology at the forefront of aging research and NCD prevention.

Keywords:  bioactive compounds; chronic diseases; fasting; metabolic dysfunction; metabolic health; oxidative stress; redox homeostasis; reduced glutathione

DOI:  https://doi.org/10.3390/ijms27146400
J Appl Physiol (1985). 2026 Jul 28.

Sex Hormones and Menopause Hormone Therapy Predict Muscle Strength Across the Lifespan.

Rachel N Logue Cook, Adina F Turcu, Carrie A Karvonen-Gutierrez, Sandra K Hunter.

  Aging is associated with declines in muscle strength, yet after menopause the relative rate of decline is greater in females than males. Whether sex hormones are predictive of strength across the lifespan and with aging is largely unknown. This study assessed the impact of sex hormone concentrations and menopause hormone therapy (MHT) on muscle strength in aging. Hand grip strength, sex hormone concentrations (total testosterone, bioavailable testosterone (FAI), estradiol, bioavailable estradiol (FEI)), and history of female MHT use were extracted or calculated from the National Health and Nutrition Examination Survey (NHANES) for 4,330 participants (2,194 females). Males were 36-40% stronger than females throughout adulthood. One-year averages of total testosterone (r=0.48, p<0.01), FAI (r=0.86, p<0.001), and FEI (r=0.71, p<0.001) were associated with strength in males. All hormones were correlated with strength in females, with estradiol (r=0.81, p<0.001) and FEI correlations (r=0.82, p<0.001) the strongest. Multiple linear regressions demonstrated that the FAI was a predictor of strength, while total testosterone was not, in both males and females and that estradiol and FEI were indicative of female strength in later adulthood. Hand grip strength in older females with a history of MHT use was 1.9kg greater than those with no MHT history (p<0.01) and this advantage widened with age (2.4% at 60 yrs to 14.3% at ≥80 yrs). This study strongly suggests (1) age-related declines in endogenous sex hormones, particularly bioavailable hormones, contribute to strength reductions with aging; and (2) MHT may have the potential to offset meaningful strength reductions with advanced aging.

Keywords:  aging; estradiol; grip strength; sex difference; testosterone

DOI:  https://doi.org/10.1152/japplphysiol.00366.2026
Cell Signal. 2026 Jul 30. pii: S0898-6568(26)00431-6. [Epub ahead of print] 112774

A combined stimulus of acute fasting and exercise modulates hippocampal mitochondrial quality control in healthy mice.

Vivien Csikos, Brittany Hauger, Taylor Strope, Colton Lysaker, Keith Smith, Julie Allen, Colin S McCoin, John P Thyfault, Heather M Wilkins.

   BACKGROUND AND AIMS: Exercise and fasting are recognized for their ability to improve brain health and mitigate neurodegeneration. However, little is known about how these interventions acutely impact mitochondrial quality control mechanisms including mitophagy.
METHODS: We examined the effects of a single bout of fasting and exercise (FEx) on hippocampal mitochondrial function and proteomic remodeling in male and female mice. To assess in vivo autophagy dynamics, we combined proteomics with chloroquine (CQ) inhibition of autophagic flux. Mice were assigned to sedentary (Sed), fasting (F), exercise (Ex), or combined FEx groups and received unilateral intrahippocampal injections of CQ or PBS following treatments. Four hours later, hippocampi were collected for analysis.
RESULTS: LC3-II levels significantly increased in the FEx group only following CQ treatment, indicating enhanced autophagic flux. Proteomic profiling showed sedentary males failed to mount a robust response to FEx however females exhibited upregulation of proteins involved in the TCA cycle, glutathione metabolism, and oxidative phosphorylation, suggesting greater mitochondrial adaptability. Functional assays supported these findings, females showed increased complex IV activity post-FEx. The mitochondrial DNA / nuclear DNA ratio increased after FEx regardless of sex, and upstream regulator analysis predicted activation of mitochondrial biogenesis.
CONCLUSIONS: Together, these data reveal sex-specific mitochondrial remodeling in response to acute fasting and exercise. Defining these normative responses is critical for understanding how mitochondrial adaptability shapes resilience or vulnerability to neurological challenges.

Keywords:  Brain; Exercise; Fasting; Mitochondria; Mitophagy

DOI:  https://doi.org/10.1016/j.cellsig.2026.112774
Antioxidants (Basel). 2026 Jun 29. pii: 819. [Epub ahead of print]15(7):

Is Ergothioneine an Important Source of Plasma Trimethylamine N-Oxide in Humans?

Irwin K Cheah, Lik Hang Wu, Richard M Y Tang, Ulrike Rieprecht, Leroy Sivappiragasam Pakkiri, Arthur Mark Richards, Chester Lee Drum, Barry Halliwell.

  High circulating levels of trimethylamine-N-oxide (TMAO), largely produced by hepatic oxidation of gut-microbiota-derived trimethylamine (TMA), are associated with increased risk of cardiometabolic and neurodegenerative diseases. In contrast, the diet-derived compound ergothioneine (ET) possesses cytoprotective and neuroprotective properties, and higher circulating ET levels have been linked to a lower risk of cardiovascular, neurodegenerative, and other age-related disorders. However, concerns have been raised that microbial degradation of ET may also contribute to the TMAO pool. In this study, we examined the relationship between ET and TMAO. Bioinformatic analyses indicated that ergothionase, the enzyme responsible for ET degradation to trimethylamine (TMA), is restricted to a limited number of bacterial genera and is far less prevalent than choline trimethylamine lyase, which generates TMA from choline. In a randomised, placebo-controlled human study, ET supplementation (25 mg/day for 7 days) significantly increased plasma ET levels but did not increase TMAO concentrations. Similarly, in a heart failure cohort, plasma ET showed no correlation with TMA or TMAO levels, whereas TMAO was clearly correlated with TMA. Collectively, these findings suggest that ET is unlikely to contribute significantly to systemic TMAO levels.

Keywords:  ergothionase; ergothioneine; gut microbiota; neurodegeneration; trimethylamine; trimethylamine-N-oxide

DOI:  https://doi.org/10.3390/antiox15070819
Geroscience. 2026 Jul 29.

Epigenetic aging biomarkers in dietary geroscience: feasibility, participant perceptions, and trial design considerations.

Lindsay M Reynolds, Timothy D Howard, Carl D Langefeld, Mara Z Vitolins.

  Targeting biological processes of aging is a central goal of geroscience; however, limited data exist regarding the feasibility of incorporating biological aging biomarkers into dietary intervention trials. We conducted a pilot feasibility study among 34 adults aged 48-81 years with metabolic syndrome, a condition associated with elevated risk of age-related cardiometabolic disease and advanced biological aging. Participants consumed 1 oz of tree nuts and two tablespoons of extra virgin olive oil daily for 4 weeks. The primary objectives were to evaluate feasibility, adherence, and participant acceptability of epigenetic aging assessments. Exploratory outcomes included DunedinPACE, a measure of the pace of aging, and AgeAccelGrim, a measure of biological age relative to chronological age. At baseline, all participants exhibited a faster pace of biological aging than average as assessed by DunedinPACE, supporting metabolic syndrome as a promising target population for geroscience interventions. Adherence to the dietary intervention exceeded 95%, and most participants reported willingness to participate in a similar longer-term trial. Participants expressed a strong interest in learning their biological age and indicated that evidence of slowed aging would motivate sustained dietary change. No significant changes in epigenetic aging were observed over the 4-week intervention. These findings demonstrate the feasibility and acceptability of incorporating epigenetic aging biomarkers into dietary intervention research and suggest that biological aging measures may serve not only as surrogate outcomes but also as tools to support participant engagement. The results also support metabolic syndrome as a relevant population for dietary geroscience trials and provide practical guidance for designing longer-term studies evaluating whether dietary interventions can slow biological aging and promote healthy longevity. ClinicalTrials.gov Identifier: NCT04361617 (date of registration: 04-23-2020).

Keywords:  Biological aging; Dietary intervention; Epigenetic aging; Extra virgin olive oil; Geroscience; Mediterranean diet; Metabolic syndrome; Tree nuts

DOI:  https://doi.org/10.1007/s11357-026-02443-0
Commun Biol. 2026 Jul 27. pii: 979. [Epub ahead of print]9(1):

Energy paradox in REM sleep: balancing supply and consumption in brain metabolism.

Yusuke Takahashi, Yoko Ikoma, Ko Matsui.

The brain's capacity for information processing depends on precisely regulated energy dynamics. Yet how metabolic supply adapts to shifting computational demands across brain states remains unclear. Using wide-field fluorescence imaging through the intact skull of live mice, we simultaneously monitored brain blood volume (BBV), astrocytic pyruvate, and neuronal ATP levels during natural sleep. We found that large-scale metabolic dynamics are coupled to neuronal activity but reorganize in a state-dependent manner. During non-rapid eye movement (NREM) sleep, theta-band electrocorticogram (ECoG) activity predicted subsequent blood volume changes, accompanied by rapid anterior-to-posterior vascular waves. In contrast, REM sleep was marked by a pronounced increase in BBV, originating in the posterior cortex and slowly propagating across the brain. This was accompanied by elevated astrocytic pyruvate; paradoxically, however, neuronal ATP levels declined sharply. These findings reveal a dynamic interplay among neurons, astrocytes, and the vasculature, suggesting that distinct energy-allocation strategies underlie the brain's computational flexibility.

DOI: https://doi.org/10.1038/s42003-026-10646-6
Exp Gerontol. 2026 Jul 25. pii: S0531-5565(26)00229-9. [Epub ahead of print]223 113250

SIRT3 inhibition promotes age-associated vascular impairment by mediating mitochondrial dysfunction and endothelial-to-mesenchymal transition.

Shiye Ke, Huijun Yang, Weifeng Lu, Lin Wu, Yuzhen Zhang, Xiaoxian Qian, Yanming Chen.

   BACKGROUND: Vascular aging profoundly impacts on cardiovascular disease. Sirtuin 3 (SIRT3) is a key regulator of metabolic homeostasis whose expression declines with age; however, the mechanisms linking SIRT3 deficiency to age-associated vascular impairment remain unclear. Here, we investigated whether SIRT3 deficiency drives age-associated vascular impairment by inducing mitochondrial dysfunction and initiating endothelial-to-mesenchymal transition (EndMT).
METHODS: Vascular morphology, aging-related protein expression, and endothelium-dependent vasorelaxation were evaluated in young (5-month-old) and aged (21-month-old) wild-type mice, alongside Sirt3 knockout (KO) mice. EndMT was assessed using immunofluorescence and immunoblotting. Mitochondrial function was examined by assessing mitochondrial morphology, determining the protein expression of mitochondrial biogenesis-related factors and superoxide dismutase 2, and measuring mitochondrial reactive oxygen species levels. In vitro, human umbilical vein endothelial cells (HUVECs) were transfected with SIRT3-targeting siRNA and treated with H2O2 to induce premature senescence, after which mitochondrial function and EndMT marker levels were analyzed.
RESULTS: Vascular aging was characterized by increased expression of aging-related proteins, endothelial dysfunction, and medial calcification and fibrosis, which were linked to EndMT and mitochondrial dysfunction in aged endothelial cells (ECs). SIRT3 expression was downregulated in aging vascular ECs. Sirt3 KO mice exhibited exacerbated vascular calcification and fibrosis, associated with the promotion of aging-induced EndMT and the aggravation of mitochondrial dysfunction. Silencing SIRT3 in prematurely senescent HUVECs confirmed its role in driving EndMT and mitochondrial dysfunction.
CONCLUSIONS: SIRT3 deficiency promotes age-related vascular impairment potentially by mediating EndMT and mitochondrial dysfunction, Thus, SIRT3 represents a potential therapeutic target for delaying vascular aging and associated cardiovascular diseases.

Keywords:  Endothelial-to-mesenchymal transition; Mitochondrial dysfunction; Sirtuin 3; Vascular aging

DOI:  https://doi.org/10.1016/j.exger.2026.113250
Neurol Ther. 2026 Jul 31.

Harnessing Brain Age-Specific Effects on the Associations Between Sleep Quality, Glymphatic Function, and Cognition in Normal Ageing Adults: Insights for Gerotherapeutics.

Hanna Lu, Zeyan Li, Liwei Guo, Xi Ni, Ben Chen, Xiaomei Zhong, Yanling Zhou, Yuping Ning.

   INTRODUCTION: The interplay between glymphatic function and sleep quality is crucial for brain health and cognitive longevity in late adulthood. Beyond chronological age, whether brain age has specific effects on the associations between glymphatic function, sleep quality, and cognition are understudied in cognitive unimpaired adults.
METHODS: Structural and diffusion magnetic resonance imaging (MRI) data from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) project (N = 582, age range 18-87 years) were used to calculate brain age metrics and the diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index. Brain age metrics comprised estimated brain age and the brain predicted age difference (brain-PAD). Subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Cognitive assessments included accuracy, reaction time, intraindividual variability of reaction time, and fluid intelligence.
RESULTS: Leftward asymmetry of the DTI-ALPS index was consistently observed across brain age-specific groups. The brain-PAD score was significantly correlated with a lower left DTI-ALPS index. Adults with a positive brain-PAD score exhibited a robust correlation between DTI-ALPS indices and sleep quality features, whereas those with a negative brain-PAD score showed a reliable correlation between DTI-ALPS indices and cognition. Mediation analyses further revealed that the relationship between left DTI-ALPS index and sleep efficiency was mediated by brain age.
CONCLUSION: This study provides the first demonstration that lateral differences in the DTI-ALPS index vary according to brain ageing statuses. The two distinct profiles of the sleep-glymphatic function-cognition connections observed in relation to brain-PAD scores suggest that a preserved brain age may serve as a protective factor against age-related decline in glymphatic function. These findings may underscore the translational potential of brain age models as both clinical biomarkers and modifiable targets for interventions aimed at promoting healthy longevity and brain resilience.

Keywords:  Brain age; Cognition; DTI-ALPS; Glymphatic function; Sleep efficiency; Sleep quality

DOI:  https://doi.org/10.1007/s40120-026-00999-9
Front Cell Dev Biol. 2026 ;14 1872070

Rutin rescues oocyte developmental competence in primary ovarian insufficiency by restoring mitophagy and suppressing pyroptosis.

Ying Zhao, Zhuo Yang, Chenyun Miao, Yuanyuan Zhang, Wenjun Xiao, Ruye Wang, Yun Chen, Ning Ren, Liuqing Yang, Haimo Qian, Heng Dai, Xiaoyi Zhu, Qin Zhang, Jing Ma.

  Primary ovarian insufficiency (POI) is a major cause of female infertility and endocrine dysfunction, for which effective therapies remain limited. We investigated whether rutin, a bioactive compound from traditional Chinese medicine, protects ovarian function in POI by regulating mitochondrial homeostasis and pyroptosis. In vitro assays using chemically injured oocytes showed that rutin alleviated mitochondrial defects, rescued developmental arrest, enhanced antioxidant signaling, promoted mitophagy, and reduced inflammatory cell death. In a cyclophosphamide-induced murine POI model, rutin restored estrous cyclicity, improved follicle development, normalized hormone levels, and enhanced ovulation, litter outcome, and in vitro-fertilization (IVF)-related developmental competence. Ovarian histological and molecular analyses further showed reduced inflammasome-related pyroptotic signaling, lower oxidative stress levels, and improved mitochondrial integrity. These findings identify rutin as a promising ovarian-protective candidate in POI-associated infertility and support further investigation of its therapeutic potential in female reproductive disorders.

Keywords:  mitophagy; oxidative stress; primary ovarian insufficiency; pyroptosis; rutin

DOI:  https://doi.org/10.3389/fcell.2026.1872070