bims-mistre 2026-08-30 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–08–30
thirty papers selected by
Ellen Siobhan Mitchell, MitoQ

Understanding cardiovascular aging as a disorder of mitochondrial network.
The Role of Skeletal Muscle Mitochondria in NLRP3 Inflammasome Signaling.
Topical Menaquinone‑7 (Vitamin K2, MK-7) as a Mitochondrial Bioenergetic Activator for Skin Anti-Aging: Mechanistic Evidence in Skin Cells and a Randomized Split-Face/Neck Study.
Pyrroloquinoline Quinone Improves Cognitive-Related Behavioral Performance Associated with Enhanced Mitochondrial Bioenergetics in Naturally Aged Mice.
MitoQ Has Diverse Effects on H2O2-Induced Oxidative Stress and the NRF2 Signalling Pathway in Aortic Smooth Muscle Cells of Different Origins.
Sex-specific effects of resveratrol and metformin on mitochondrial function and inflammatory activation in a TNF-α-driven human iPSC-derived endothelial dysfunction model.
cGAS-STING signaling in aging and age-related diseases: therapeutic promise and precaution.
Reverse electron transport connects tauopathy to mitochondrial dysfunction.
Nanoliposomal curcumin protects against D-galactose-induced hepatic aging by targeting oxidative stress, mitochondrial dysfunction, and inflammatory signaling.
Nicotinamide Mononucleotide (NMN) Prevents Age-Associated Transcriptional Drift in a Tissue-Dependent Manner: Mechanistic Leads From Ras-Related Protein Rab-11A-Mediated Trafficking and Carnitine Palmitoyltransferase 2-Linked Fatty Acid Oxidation.
Mitochondrial DNA leakage in oocytes activates cGAS-STING signaling to drive ovarian aging.
Targeting Oxidative Stress in Insulin-Resistant Postmenopausal Women: Effects of Resveratrol and Vitamin C on Oxidative Damage and Antioxidant Defenses in a Randomized Clinical Trial.
Oxygenaging: A Physiological Framework for Geroscience.
Mitochondria in SARS-CoV-2 infection: Immune interactions and molecular approaches in the Post COVID-19 condition.
Targeting Bioenergetic, Redox and Prostaglandin Pathways in Long COVID-Associated Post-Exertional Malaise and Brain Fog: A Nutraceutical Translational Hypothesis.
Proof of Principle: Short-Term Sulforaphane Precursor Intake Alters Selected Circulating Oxidative Stress and Muscle Damage Biomarkers Following Maximal Exercise: A Double-Blind Crossover Trial.
Emerging microbiome-mitochondria crosstalk in host defense and infectious diseases: mechanistic insights into NLRP3 inflammasome activation and mtDNA-mediated immunomodulation.
Early life predictors of subjective cognitive function in older age: Emerging longitudinal associations over six decades.
Mitochondria as a therapeutic platform in inflammatory and degenerative disorders: mechanisms, biomarkers, and translational challenges.
Adipose FGF21 signalling mediates the anti-senescence effects of protein restriction.
Dietary Intervention With Lutein, Docosahexaenoic Acid, and Choline During Early Development Improves Recognition Memory in Young Adult Females in an Experimental Model.
Orally administered scallop-derived plasmalogens improve cognitive function in healthy middle-aged and older adults: a randomized, double-blind, placebo-controlled trial.
Time-dependent and partially reversible mitochondrial remodeling induced by coenzyme Q10 depletion in HepG2 cells.
Vasomotor Symptoms and Their Association with Depressive and Anxiety Symptoms in Peri- and Postmenopausal Women: A Systematic Review of Observational Studies.
Impact of N-PEP-12 Supplementation on Attentional Performance and Mental Wellbeing in Healthy Adults with Subjective Cognitive Complaints: A Randomized, Placebo-Controlled Trial.
The multisystem impact of perimenopausal hormonal fluctuations on chronic disease risk.
Potential effects of β-hydroxy-β-methylbutyrate and exercise on brain aging and age-related disorders: implications for immunometabolic regulation and muscle-brain-immune crosstalk.
Mitochondrial regulation of cellular senescence heterogeneity.
Erucic acid arbitrates neuroprotection in streptozotocin-induced memory deficit via improving oxidative stress/neuroinflammatory indicators/cholinergic activity in rodents.
Pyrroloquinoline Quinone (PQQ) as a Mitochondrial Rejuvenation Strategy in Aesthetic Dermatology: Mechanisms, Therapeutic Potential, and Future Clinical Applications.

J Cardiovasc Aging. 2026 ;pii: 12. [Epub ahead of print]6(2):

Understanding cardiovascular aging as a disorder of mitochondrial network.

Taslima Akter Shila, Dhrubo Ahmad, Jianli Zhao, Huilan Tan, Bo Wang, John Zhang, Yajing Wang.

  Cardiovascular aging is increasingly recognized as a mitochondrial-initiated systemic network dysfunction, a progressive, integrative failure driven by deteriorating mitochondrial quality and signaling. This review synthesizes emerging evidence linking comprehensive mitochondrial pathology to the erosion of cardiovascular resilience as a network-level dysfunction. Age-dependent remodeling of mitochondrial ultrastructure and component composition disrupts respiratory efficiency, positioning bioenergetic insufficiency as a central determinant of reduced stress tolerance across the cardiovascular system. Concurrently, defects in mitochondrial fission-fusion dynamics and impaired mitophagy propagate dysfunction within the mitochondrial network, amplifying the decline in energetic capacity. Beyond energy failure, the release of mitochondrial DNA, vesicles, and peptides activates innate immune sensors such as the cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthase-stimulator of interferon genes (cGAS-STING) pathway, initiating chronic sterile inflammation that propagates maladaptive remodeling cascades throughout cardiovascular tissues and distal organs. We challenge the traditional view of mitochondria solely as energy producers, revealing that uncoupled perfusion and energy metabolism, together with nitric oxide imbalance, can serve as early indicators of diastolic dysfunction and ischemic susceptibility. Additionally, we introduce the concept of "mitochondrial age", a composite measure that integrates respiratory function, imaging-based structural indices, and circulating mitochondrial biomarkers to quantify mitochondrial health. This metric may serve as a translational tool for assessing cardiovascular aging through mitochondrial network communication. Finally, we highlight rejuvenation strategies aimed at restoring mitochondrial youthfulness, ranging from behavioral interventions (exercise, time-restricted feeding) to metabolic and molecular therapies targeting nicotinamide adenine dinucleotide (NAD+) metabolism, mitophagy, and endothelial mitochondrial protection. Collectively, this review defines cardiovascular aging as a network-level mitochondrial disorder, offering new conceptual and therapeutic directions for preserving cardiac and vascular function.

Keywords:  Cardiovascular aging; endothelial dysfunction; epidemiology; heart failure with preserved ejection fraction; hypertension; mitochondrial dysfunction; mitophagy

DOI:  https://doi.org/10.20517/jca.2026.07
Biomolecules. 2026 Aug 20. pii: 1218. [Epub ahead of print]16(8):

The Role of Skeletal Muscle Mitochondria in NLRP3 Inflammasome Signaling.

Jada Sangha, David A Hood.

  Skeletal muscle mitochondria possess the ability to autoregulate their health and functioning by the orchestration of mitochondrial quality control (MQC) pathways. This plasticity allows them to adapt to various stimuli, such as exercise. However, under pathological conditions, mitochondria can become dysfunctional, generating damage-associated molecular patterns (DAMPs), such as reactive oxygen species (ROS) and oxidized mitochondrial DNA (mtDNA). These DAMPs can launch an innate immune response, with consequences of widespread inflammation and atrophy. Integral to this is the NLRP3 inflammasome complex. Activation of the NLRP3 inflammasome results in maturation of caspase-1, which processes pro-inflammatory cytokines IL-1β and IL-18, as well as GSDMD. Consequently, the pore-forming GSDMD-N fragment induces pyroptosis, releasing mature IL-1β and IL-18. Exercise training is widely accepted as a potent mechanism to promote skeletal muscle health, particularly by remodeling the mitochondrial network and reducing the production of DAMPs. It has also been shown promote an anti-inflammatory milieu with the release of various myokines. Indeed, the potential of exercise to mitigate NLRP3 inflammasome-mediated inflammation and atrophy is promising. This review will examine the mechanisms underpinning inflammasome priming and activation, as well the effects of exercise, with an emphasis on the skeletal muscle.

Keywords:  NLRP3 inflammasome; exercise; inflammation; mitochondria; mtROS; muscle atrophy; skeletal muscle

DOI:  https://doi.org/10.3390/biom16081218
ACS Omega. 2026 Aug 25. 11(33): 49613-49625

Topical Menaquinone‑7 (Vitamin K2, MK-7) as a Mitochondrial Bioenergetic Activator for Skin Anti-Aging: Mechanistic Evidence in Skin Cells and a Randomized Split-Face/Neck Study.

He Huang, Ruijing Wei, Chunxiao Xu, Chen Liu, Shilan Zhao, Yanan Li, Meijing Wang.

Mitochondrial dysfunction contributes to skin aging by limiting cellular energy supply, shifting redox balance, and amplifying oxidative injury, which together favor extracellular matrix breakdown and loss of tissue mechanics. Vitamin K2 (menaquinone-7; MK-7) has been proposed to support mitochondrial electron transport, yet its bioenergetic activity in the skin and its effects on aging-related outcomes remain insufficiently characterized. To evaluate whether MK-7 can improve mitochondrial bioenergetics in skin-relevant cells under oxidative stress and whether these effects translate into quantifiable anti-aging benefits in a controlled human study. In vitro , human skin cells were exposed to UVA or hydrogen peroxide to model oxidative stress and then treated with MK-7. ATP content, NAD+/NADH ratio, mitochondrial membrane potential ( ΔΨm ), mitochondrial DNA (mtDNA) copy number, respiratory chain complex activities (I-V), and senescence-associated secretory phenotype (SASP) expression were assessed using established assays. In vivo , a randomized, double-blind, split-face/neck, vehicle-controlled trial enrolled women aged 35-60 years (n = 30 completers). Participants applied a 0.05% MK-7 face-and-neck cream to one randomized side and placebo to the contralateral side twice daily for 8 weeks. Wrinkles/roughness, elasticity, and sagging were instrumentally quantified at baseline and weeks 2, 4, and 8. MK-7 increased ATP production, elevated the NAD+/NADH ratio, restored ΔΨm , preserved mtDNA copy number under oxidative challenge, enhanced activities of multiple respiratory complexes, and reduced UVA-induced SASP marker expression. In human efficacy evaluations, MK-7 produced significant improvements versus placebo in wrinkle roughness on face and neck, improved elasticity parameters, and attenuated sagging over 8 weeks. MK-7 was associated with improved mitochondrial bioenergetic readouts in vitro and measurable anti-aging effects in a split-face/neck study, supporting further development of mitochondrial targeting approaches for skin aging.

DOI: https://doi.org/10.1021/acsomega.6c03314
Antioxidants (Basel). 2026 Jul 24. pii: 921. [Epub ahead of print]15(8):

Pyrroloquinoline Quinone Improves Cognitive-Related Behavioral Performance Associated with Enhanced Mitochondrial Bioenergetics in Naturally Aged Mice.

Yun Yan, Di Deng, Chunxia Tan, Qi Lu, Jiutang Sun, Shaoliang Wu, Zhanhua Jiang, Yibo Li, Tao Lu.

  We investigated whether pyrroloquinoline quinone (PQQ) could improve cognitive performance in twenty-month-old naturally aged mice and explored the potential mechanisms involved. Results showed that PQQ supplementation improved spatial working memory and recognition memory without inducing anxiety-like behavior, and was associated with better preservation of hippocampal neuronal integrity. In HT-22 hippocampal neuronal cells, PQQ reduced reactive oxygen species (ROS) accumulation, restored mitochondrial membrane potential, and enhanced mitochondrial respiratory capacity. Hippocampal transcriptomic analysis and upstream regulator prediction identified sirtuin 1 (SIRT1) as a major regulator associated with the PQQ-induced transcriptional response, while uncoupling protein 2 (UCP2) emerged as a candidate downstream mitochondrial effector. Consistently, PQQ increased hippocampal SIRT1 protein expression and downregulated UCP2 at both mRNA and protein levels. Pharmacological inhibition of SIRT1 attenuated the PQQ-induced increase in ATP production and partially weakened the regulatory effect of PQQ on UCP2, supporting the involvement of SIRT1 in PQQ-associated mitochondrial bioenergetic regulation. Collectively, these findings indicate that PQQ improves cognitive-related behavioral performance in naturally aged mice and is associated with mitochondrial bioenergetic regulation, and suggest that modulation of a SIRT1-UCP2-associated pathway may contribute to its neuroprotective effects.

Keywords:  cognitive decline; mitochondria function; natural aging; oxidative stress; pyrroloquinoline quinone

DOI:  https://doi.org/10.3390/antiox15080921
Cells. 2026 Aug 20. pii: 1499. [Epub ahead of print]15(16):

MitoQ Has Diverse Effects on H2O2-Induced Oxidative Stress and the NRF2 Signalling Pathway in Aortic Smooth Muscle Cells of Different Origins.

Simon Cornelius Haas, Bingchen Hou, Andreas Sebastian Peters, Johannes Hatzl, Dittmar Böckler, Susanne Dihlmann.

  Oxidative stress plays a central role in the development and progression of abdominal aortic aneurysms (AAA), as it severely impairs the function and survival of vascular smooth muscle cells (VSMCs). MitoQ (mitoquinone mesylate), a mitochondria-specific antioxidant, was shown to reverse age-related arterial stiffening and improve vascular endothelial function, among other things, by interacting with the NRF2 signalling pathway. The aim of this study was to compare how long-term treatment with low doses of MitoQ affects the NRF2 stress response in VSMCs, derived from different origins (AAA-SMC, healthy aortic SMC, and immortalized VSMC (iHAoSMC)). We found a significant reduction in NRF2 and KEAP1 levels in the aortic wall of patients with AAA, accompanied by increased 8-OHdG levels, indicating defects in the response to oxidative stress. In contrast, relative NRF2 expression in tissue extracts and VSMC-enriched areas was higher in patients with AAA than in healthy aortic tissue. In vitro, baseline NRF2 protein levels were significantly higher in AAA-SMC and in iHAoSMC than in VSMC from healthy aorta, whereas NRF2 activity did not differ between AAA-derived and healthy VSMC. AAA-derived SMC were found to be less vulnerable against toxic concentrations of MitoQ than healthy VSMC, and the cell viability was differentially affected by H2O2. Acute oxidative stress by H2O2 increased NRF2 activity in AAA-SMC and iHAoSMC, but not in healthy VSMC. Pre-treatment of the cells for 7 days with low-dose (10 nM) MitoQ resulted in significantly increased NRF2 activity in AAA-SMC and iHAoSMC, but not in healthy VSMC, which was accompanied by a significant reduction of ROS production, particularly in AAA-derived SMC. Our data demonstrate that prolonged treatment with low doses of MitoQ has a protective effect, particularly on VSMCs from AAA, without affecting healthy aortic VSMCs. Moreover, immortalized cells can be used as a model for investigating oxidative stress responses in AAA-SMC, even though they do not react in exactly the same way. Overall, our findings confirm the cytoprotective potential of MitoQ to limit oxidative stress, particularly in AAA-SMC that is clinically observed in the abdominal aneurysm wall.

Keywords:  MitoQ; NRF2 signalling; abdominal aortic aneurysm; mitoquinone mesylate; oxidative stress; vascular smooth muscle cells

DOI:  https://doi.org/10.3390/cells15161499
Front Immunol. 2026 ;17 1903774

Sex-specific effects of resveratrol and metformin on mitochondrial function and inflammatory activation in a TNF-α-driven human iPSC-derived endothelial dysfunction model.

Julia Temp, Elisabeth Tamara Strässler, Julia Freitag, Haiyan Wu, Natalie Haritonow, Ulf Landmesser, Sofya Podzniakova, Maria Luisa Barcena.

  Endothelial dysfunction and mitochondrial impairment are key early events in atherogenesis and exhibit sex-specific patterns. Resveratrol and metformin are cardiometabolic modulators with antioxidative and mitochondrial effects, but their sex-dependent actions in human iPSC-derived endothelial cells (iPSC-EC) remain unclear. iPSC-EC generated from peripheral blood mononuclear cells of six male and six female donors were stimulated with TNF-α to induce a pro-atherogenic phenotype and subsequently treated with resveratrol or metformin. Mitochondrial ROS production, mitochondrial content, endothelial permeability, mitochondrial respiration, inflammatory mediators and LDH release were quantified in a sex-stratified manner. In this TNF-α-driven human iPSC-EC inflammatory dysfunction model, male iPSC-EC displayed stronger mitochondrial superoxide signal, inflammatory activation and endothelial barrier disruption, whereas female iPSC-EC showed a trend towards impaired mitochondrial respiration and reduced IL-10. Resveratrol and metformin trend towards reduced selected TNF-α associated endothelial injury markers. Resveratrol and metformin attenuated TNF-α-associated oxidative stress, cytokine secretion, permeability and LDH release, with male cells mainly benefiting from decreased mitochondrial superoxide signal and inflammation, and female cells showing non-significant tendencies towards improved mitochondrial respiration and restoration of IL-10. These findings highlight cellular sex as a critical determinant of endothelial immunometabolic responses to inflammatory stress and suggest that resveratrol- and metformin-based strategies for vascular protection should be evaluated in a sex-aware manner.

Keywords:  iPSC-EC; immunometabolic responses; inflammatory dysfunction model; metformin; resveratrol; sex differences

DOI:  https://doi.org/10.3389/fimmu.2026.1903774
Arch Pharm Res. 2026 Aug 24.

cGAS-STING signaling in aging and age-related diseases: therapeutic promise and precaution.

Yingying Xu, Weidong Wu, Yifan Guo, Wenhong Wang, Jingsheng Zhu, Weihua Xiao.

  Endogenous cytoplasmic DNA (cytoDNA) is increasingly recognized as a mediator of tissue dysfunction and disease progression during aging. As a major cytosolic DNA-sensing pathway, the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway can translate aging-associated cytoDNA accumulation into innate immune and inflammatory programs. This review summarizes the evolutionary and signaling features of the cGAS-STING cascade and critically discusses its crosstalk with aging-associated intracellular molecular threats, including nuclear genomic and chromatin stress, mitochondrial dysfunction, oxidative-metabolic stress, and defective clearance of nucleic acids or damaged organelles. We further synthesize evidence linking dysregulated cGAS-STING activation to inflammatory remodeling, senescence-associated changes, cell injury, fibrosis, and tissue dysfunction, while highlighting the context-dependent roles of this pathway across physiological aging and ARDs. Finally, we discuss the therapeutic potential and limitations of cGAS-STING modulation, emphasizing that successful translation will require context-defined therapeutic windows, tissue- and cell-specific targeting, subcellular compartmentalization, and long-term safety assessment.

Keywords:  Aging-related diseases; Cytosolic DNA; Therapeutic modulation; cGAS–STING signaling

DOI:  https://doi.org/10.1007/s12272-026-01633-w
Nat Rev Neurol. 2026 Aug 27.

Reverse electron transport connects tauopathy to mitochondrial dysfunction.

Heather Wood.

DOI: https://doi.org/10.1038/s41582-026-01265-0
J Pharm Pharmacol. 2026 Aug 03. pii: rgag087. [Epub ahead of print]78(8):

Nanoliposomal curcumin protects against D-galactose-induced hepatic aging by targeting oxidative stress, mitochondrial dysfunction, and inflammatory signaling.

Ekramy M Elmorsy, Ayat B Al-Ghafari, Huda A Al Doghaither, Syed Sajid Hussain Shah, Asmara Syed, Muhammad Jan, Eman M Embaby, Eman E Elwakeel.

   OBJECTIVES: With advancing age, individuals experience a decline in liver function, an increase in oxidative stress, and diminished mitochondrial efficiency. This research examined the protective effects of curcumin (CUR), in both free and nanoliposomal (CUR-LNP) forms, against D-galactose (D-gal)-induced liver aging in male Wistar rats.
METHODS: Rats were assigned to six groups: control, CUR, CUR-LNPs, D-gal, D-gal+CUR, and D-gal+CUR-LNPs. CUR and CUR-LNPs (40 mg/kg) and D-gal (150 mg/kg) were administered orally for 10 weeks. Liver function, lipid profile, oxidative stress (GSH, CAT, SOD, and NRF2/HO-1), mitochondrial function (ATP and respiratory complexes), inflammation (NF-κB, TNF-α, IL-1β, IL-6, and iNOS), and apoptosis (caspases, Bax/Bcl-2) were assessed. Histological and ultrastructural analyses were also performed.
KEY FINDINGS: D-gal induced hepatic injury, oxidative stress, mitochondrial dysfunction, inflammation, and apoptosis. CUR partially attenuated these alterations, whereas CUR-LNPs produced greater protection by restoring liver enzymes and lipid homeostasis, enhancing antioxidant and mitochondrial functions, suppressing NF-κB signaling and inflammatory mediators, and reducing apoptotic markers. Histological and ultrastructural analyses confirmed preserved hepatocyte and mitochondrial architecture.
CONCLUSION: CUR, especially in its nanoliposomal form, exerts potent hepatoprotective, antioxidant, anti-inflammatory, and anti-apoptotic effects against D-gal-induced liver aging, supporting its potential as a therapeutic strategy for age-related hepatic dysfunction.

Keywords:  D-galactose; apoptosis; curcumin; inflammation; liposomal nanoparticles; liver aging; mitochondrial function; oxidative stress

DOI:  https://doi.org/10.1093/jpp/rgag087
Cureus. 2026 Aug;18(8): e114956

Nicotinamide Mononucleotide (NMN) Prevents Age-Associated Transcriptional Drift in a Tissue-Dependent Manner: Mechanistic Leads From Ras-Related Protein Rab-11A-Mediated Trafficking and Carnitine Palmitoyltransferase 2-Linked Fatty Acid Oxidation.

Ngo Cheung.

  This study is a secondary computational reanalysis of the publicly available GSE85718 microarray dataset generated during the long-term nicotinamide mononucleotide (NMN) study. NMN has been reported to improve several age-sensitive physiological traits in mice, including energy metabolism, insulin sensitivity, plasma lipid profiles, and skeletal-muscle mitochondrial function. However, the transcriptional mechanisms behind these effects remain less clear than the broader nicotinamide adenine dinucleotide (NAD+) and sirtuin-centered model often used to explain NMN biology. The present analysis used a per-tissue age-by-treatment interaction model to test whether NMN modifies the rate of age-associated transcriptional change rather than simply shifting expression at one age. The model was expression ~ age × treatment, with the age-by-treatment term used as the central test. A gene was considered an NMN-rescue candidate only when it changed with age in control mice and showed an opposite-signed interaction term, consistent with NMN shifting old-age expression toward the young-control state. No individual gene reached genome-wide false discovery rate (FDR) <0.05 for age, NMN at six months, or the interaction term in skeletal muscle, liver, or white adipose tissue (WAT). Therefore, all gene-level results should be treated as hypothesis-generating. Using relaxed nominal criteria, 421 rescue candidates were identified in skeletal muscle, 355 in liver, and 397 in WAT. Only 35 genes were rescued in at least two tissues, 26 of which were direction-consistent, and none were rescued in all three tissues. Ras-related protein Rab-11A (RAB11A) emerged as the strongest cross-tissue candidate, with rescue in skeletal muscle and WAT, high confidence in at least one tissue, consistent directionality, and involvement in 39 gene set enrichment analysis (GSEA) leading-edge terms, largely related to trafficking and cellular transport. Carnitine palmitoyltransferase 2 (CPT2) was the only mitochondrial gene among the robust cross-tissue candidates and was consistently rescued in skeletal muscle and WAT, supporting a focused fatty-acid oxidation and substrate-handling hypothesis rather than broad mitochondrial activation. At the pathway level, liver showed the clearest signal: NMN was associated with suppression of fatty-acyl-coenzyme A (CoA) and long-chain fatty-acyl-CoA metabolic programs. These findings do not establish that NMN prevents transcriptional aging or that RAB11A or CPT2 mediates the physiological effects of NMN. Instead, they identify tissue-specific, testable candidates from a secondary reanalysis of an existing animal dataset. In particular, they support moving beyond a generic "NAD+ improves mitochondria" model toward testable mechanisms involving cellular logistics, membrane recycling, and substrate utilization.

Keywords:  age-by-treatment interaction; aging; cpt2; liver; nad+ metabolism; nmn; rab11a; skeletal muscle; transcriptional drift; white adipose tissue

DOI:  https://doi.org/10.7759/cureus.114956
Nat Aging. 2026 Aug 28.

Mitochondrial DNA leakage in oocytes activates cGAS-STING signaling to drive ovarian aging.

Min Lei, Zhenye Zhu, Huihui Xie, Chenlu Wei, Jiajia Zhu, Keer Wang, Kexin Zhang, Yongxing Yu, Linli Yang, Xiangyang Zhang, Ning Song, Diyi Xie, Ruizhi Guo, Yanqing Zhao, Aaron J W Hsueh, Yingpu Sun, Qingling Yang.

Ovarian aging precedes decline in many organs, but its mechanisms remain unclear. Here we show that aging oocytes accumulate cytoplasmic mitochondrial DNA (mtDNA) through increased mtDNA leakage, activating the cyclic GMP-AMP synthase (cGAS) pathway to produce cGAMP and trigger stimulator of interferon genes (STING) signaling. Notably, oocyte-derived cGAMP can pass through gap junctions to surrounding granulosa cells (GCs), activating STING signaling in GCs as well. To model age-associated mitochondrial dysfunction, we generated oocyte-specific Tfam-knockout mice, which recapitulated mtDNA leakage, STING pathway activation in both oocytes and GCs, inflammation and accelerated ovarian dysfunction. We also used Opa1 knockdown and Pink1 deletion oocytes as complementary mitochondrial stress models and observed mtDNA leakage and cGAS-STING activation in both settings. Notably, oocyte-specific Cgas deletion in Tfam mutants or pharmacological STING inhibition with H-151 ameliorated ovarian dysfunction. These findings establish oocyte mtDNA leakage as a causal driver of ovarian aging and nominate cGAS-STING signaling as a therapeutic target.

DOI: https://doi.org/10.1038/s43587-026-01195-y
Antioxidants (Basel). 2026 Aug 18. pii: 1028. [Epub ahead of print]15(8):

Targeting Oxidative Stress in Insulin-Resistant Postmenopausal Women: Effects of Resveratrol and Vitamin C on Oxidative Damage and Antioxidant Defenses in a Randomized Clinical Trial.

Enrique Reyes-Muñoz, Arturo Arellano-Eguiluz, Guillermo F Ortiz-Luna, Alberto M Guzmán-Grenfell, Arturo Flores-Pliego, Aurora Espejel-Nuñez, Sandra B Parra-Hernández, Elizabeth García-Gómez, José Romo-Yañez, Araceli Montoya-Estrada.

  Women experience significant changes throughout their lives, particularly during the transition from reproductive age to postmenopause, marked by hormonal imbalance and reduced estrogen production. This stage is associated with increased oxidative stress, which can contribute to cardiovascular issues and insulin resistance. This study aimed to assess the effects of resveratrol and vitamin C supplementation on 8-Isoprostane, a marker of oxidative stress, and on DNA damage, as indicated by 8-hidroxi-2'-desoxiguanosina (8-Oxo-dG), in postmenopausal women with insulin resistance, and to evaluate how these supplements modified antioxidant defense. A randomized, double-blind clinical trial was conducted. Plasma samples were analyzed to measure antioxidant enzyme activity, including superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx), and to assess oxidative damage to lipids and DNA. Forty-two patients were recruited and randomly assigned to three treatment groups. Within-group analyses showed significant increases in CAT and GR activities and a reduction in plasma 8-isoprostane concentrations in the group receiving combined resveratrol and vitamin C supplementation, with increases of 12% in CAT activity (p = 0.008) and 84% in GR activity (p = 0.007), and a 34% reduction in 8-isoprostane concentrations (p = 0.01). However, no significant between-group differences or treatment × time interactions were observed. No significant changes were detected in 8-Oxo-dG concentrations. These preliminary findings suggest that antioxidant supplementation may influence selected markers of antioxidant defense and lipid oxidative damage in postmenopausal women with insulin resistance; however, the present study does not demonstrate the superiority of one supplementation regimen over the others.

Keywords:  8-isoprostane; antioxidants; catalase; glutathione reductase; insulin resistance; polyphenol; postmenopause

DOI:  https://doi.org/10.3390/antiox15081028
Aging Cell. 2026 Sep;25(9): e70664

Oxygenaging: A Physiological Framework for Geroscience.

Stefano Donega, Kenneth W Fishbein, Paolo Dominelli, Allison B Herman, Rafael de Cabo, Myriam Gorospe, Luigi Ferrucci.

  The stepwise movement of oxygen from the atmosphere to the mitochondria, the "oxygen cascade", is one of the most tightly regulated systems in physiology. Despite decades of mechanistic study, it has remained quite unexplored in Geroscience. This oversight should be reconsidered. In young organisms, hypoxic stress (whether environmental or tissue-specific) activates a complex adaptive response to preserve energetic stability via restraining anabolic pathways, optimizing mitochondrial performance, and reinforcing cellular quality control systems. With advancing age, angiostatic signaling increases, endothelial metabolism becomes dysregulated, and overall alveolar ventilation and pulmonary gas exchange (ventilation-perfusion matching and diffusion capacity) become less efficient. These changes promote microvascular rarefaction and low-grade but persistent mismatches between oxygen delivery and demand at the tissue level, ultimately destabilizing cellular function. In this review, we propose that the gradual erosion of oxygen homeostasis is not simply a byproduct of aging, but also a driver of molecular damage and functional decline. We examine the aging oxygen cascade through the framework of resilience biology, focusing on mechanisms such as mitochondrial electron leaks, oxidative stress amplification, iron dyshomeostasis, ferroptosis, and epigenetic remodeling. We also discuss interventions that alter oxygen availability, such as intermittent hypoxia, hyperbaric oxygen therapy, and hypoxic-hyperoxic training. These approaches demonstrate adaptive potential, but they also highlight the narrow margin between beneficial stress and injury. We propose "Oxygenaging" as a unifying framework in which aging associates with the progressive loss of equilibrium across the oxygen cascade, linking systemic oxygen transport to mitochondrial function, genomic stability, and cellular resilience.

Keywords:  Oxygenaging; RNA splicing; aging; energy; epigenetics; hyperoxia; hypoxia; hypoxia inducible factor 1 (HIF1); mitochondria; oxygen

DOI:  https://doi.org/10.1111/acel.70664
Genet Mol Biol. 2026 ;pii: S1415-47572026000800109. [Epub ahead of print]49Suppl 4(Suppl 4): e20250118

Mitochondria in SARS-CoV-2 infection: Immune interactions and molecular approaches in the Post COVID-19 condition.

Maria Clara Barros, Felipe Gouvêa de Souza, Helenize Costalat, Catarina Torres Pinho, Karina Carvalho Marques, Matheus Epifane-de-Assunção, Giovanna C Cavalcante, Luiz Fábio Magno Falcão, Juarez A S Quaresma, Ândrea Ribeiro-Dos-Santos.

Mutations in mitochondrial genes can disrupt key cellular functions and contribute to the development of various complex diseases. The pandemic of COVID-19, caused by the SARS-CoV-2 infection, has been associated as the cause of certain mitochondrial dysfunctions, including physiological and genetic due to infection processes as increased release of reactive oxygen species (ROS), formation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, mitophagy impairment and mitochondrial apoptotic pathway. This review compiled the main interactions between SARS-CoV-2 infection and mitochondria, highlighting mainly the genetic and immunological mechanisms that contribute to the progression of the disease and how the persistence of this inflammatory and dysfunctional state can lead to cardiac, muscular and neurological sequelae, characterizing the post COVID-19 condition.

DOI: https://doi.org/10.1590/1678-4685-GMB-2025-0118
Nutrients. 2026 Aug 13. pii: 2650. [Epub ahead of print]18(16):

Targeting Bioenergetic, Redox and Prostaglandin Pathways in Long COVID-Associated Post-Exertional Malaise and Brain Fog: A Nutraceutical Translational Hypothesis.

Stephan F E Praet.

  Post-exertional malaise (PEM) and cognitive dysfunction (hereafter "cognitive dysfunction", including the patient-reported syndrome often described as "brain fog") are among the most disabling features of Long COVID; yet, approved disease-modifying treatments remain lacking. Emerging evidence implicates interacting disturbances in mitochondrial bioenergetics, redox regulation and neurovascular inflammation, although much of the supporting evidence remains indirect and derives from acute COVID-19, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), primary mitochondrial disease, inflammatory biology and mechanistic pharmacology rather than from direct Long COVID intervention trials. This hypothesis-generating narrative review develops a mechanism-based translational framework: that a pathway-targeted nutraceutical programme may modulate selected elements of these three axes, subject to prior demonstration of formulation quality, pharmacokinetic feasibility, target engagement and safety. Candidate modules comprise coenzyme Q10 and alpha-lipoic acid for bioenergetic/redox support; selenium, sulforaphane and resveratrol for Nrf2-thioredoxin-related redox regulation; and Boswellia serrata, luteolin and eicosapentaenoic acid for putative prostaglandin/resolution-pathway modulation. Sonlicromanol provides a conceptual mechanistic precedent for combined redox and prostaglandin-directed pharmacology, but it is not considered pharmacologically equivalent to an eight-agent nutraceutical combination. We summarise the mechanistic rationale, distinguish direct from indirect evidence, define qualitative evidence-grading criteria, outline safety and interaction considerations, and propose a staged translational research programme. This framework is intended to generate falsifiable hypotheses for future Long COVID studies, not to imply established clinical efficacy.

Keywords:  Long COVID; Nrf2; brain fog; coenzyme Q10; mPGES-1; mitochondrial dysfunction; nutraceuticals; oxidative stress; post-acute sequelae of SARS-CoV-2; post-exertional malaise

DOI:  https://doi.org/10.3390/nu18162650
Nutrients. 2026 Aug 10. pii: 2617. [Epub ahead of print]18(16):

Proof of Principle: Short-Term Sulforaphane Precursor Intake Alters Selected Circulating Oxidative Stress and Muscle Damage Biomarkers Following Maximal Exercise: A Double-Blind Crossover Trial.

Ruheea Taskin Ruhee, Shiori Wakasugi-Onogi, Sihui Ma, Nobuhiro Nakamura, Yasuhiro Seki, Katsuhiko Suzuki.

   BACKGROUND: Endurance exercise is known to induce the excessive production of reactive oxygen metabolites due to enhanced metabolic activity and inflammation, leading to oxidative stress and related injuries. Sulforaphane (SFN), an isothiocyanate, is broadly acknowledged for its potential antioxidant and anti-inflammatory properties, along with other protective functions.
OBJECTIVE: The purpose of this study was to investigate the effects of short-term SFN precursor supplementation on maximal exercise-induced muscle damage, oxidative stress and endurance capacity in healthy adults.
METHODS: In a double-blind placebo-controlled crossover design, 14 healthy participants (7 males, 7 females; age, 25.07 ± 1.04 years; weight, 65.28 ± 4.13 kg; height, 170.07 ± 3.46 cm; BMI, 22.48 ± 0.91) received SFN glucosinolate capsules (200 µmol/day) or placebo for 2 weeks during the first trial. Following a three-week washout period, the participants crossed over to the alternate treatment. Maximal exercise tests were performed following each supplementation (SFN or placebo) period. Blood samples were collected at baseline (before treatment), pre-exercise, post-exercise and 2 h after each exercise session.
RESULTS: SFN supplementation did not alter endurance capacity or blood cell counts; however, it significantly attenuated serum creatine kinase (CK) activity (p = 0.034; SFN, 121.52 ± 16.89; placebo, 291.84 ± 133.07) and the myoglobin (Mb) concentration (p = 0.011; SFN, 15.82 ± 1.95; placebo; 27.31 ± 5.71) following exercise. Analysis of oxidative stress markers showed no significant changes in the absolute values; however, in the d-ROMs (p = 0.038; SFN, 107.42 ± 2.39; placebo; 112.32 ± 2.11) and OXY-adsorbent tests (p = 0.032; SFN, 115.97 ± 4.15; placebo; 107.73 ± 3.88), the percent changes from the baseline showed a significant interaction with the supplement. These findings suggest that short-term SFN supplementation may mitigate exercise-induced muscle damage and oxidative stress, suggesting a modest influence on the circulating biomarkers associated with muscle damage without altering the endurance capacity of healthy people.
CONCLUSION: SFN intake may be a beneficial, non-invasive strategy to modulate acute biochemical responses to exercise via the antioxidant defense system in physically active individuals.

Keywords:  antioxidant; exercise; muscle damage; oxidative stress; sulforaphane

DOI:  https://doi.org/10.3390/nu18162617
Front Cell Infect Microbiol. 2026 ;16 1866924

Emerging microbiome-mitochondria crosstalk in host defense and infectious diseases: mechanistic insights into NLRP3 inflammasome activation and mtDNA-mediated immunomodulation.

Xinxing Lu, Wenbin Sun, Daowei Zhang, Bin Hou, Huiyu Tai, Wenqing Yu, Xuehua Pu.

  Recent studies highlight a complex interaction between the gut microbiome and host mitochondrial dynamics in the modulation of immune responses as well as susceptibility to infectious and inflammatory pathologies. Recent empirical studies elucidate that metabolites derived from microbiota, encompassing short-chain fatty acids, trimethylamine, and indole derivatives, orchestrate mitochondrial functionality and the production of reactive oxygen species, which subsequently affect NLRP3 inflammasome activation. Dysbiosis within the gut microbiota has been documented to aggravate mitochondrial stress in host intestinal epithelial cells and other tissue-resident cells, facilitate the release of mitochondrial DNA (mtDNA), and initiate inflammatory pathways across a spectrum of conditions, including colitis, neurodegeneration, cardiovascular disorders, and sepsis. In contrast, the application of probiotics, postbiotics, and phytochemicals may restore microbial equilibrium, bolster mitochondrial integrity through mitophagy and PINK1/Parkin pathways, and mitigate NLRP3 inflammasome-mediated pyroptosis. Furthermore, experimental findings suggest that mtDNA functions as a damage-associated molecular pattern, activating cGAS-STING and NLRP3 signaling pathways, thereby establishing a connection between alterations in microbiota and systemic inflammation. The microbiome-mitochondria axis has been further associated with organ-specific immune responses, encompassing interactions among the gut-lung, gut-brain, gut-kidney, and gut-liver systems. Notably, the liver serves as a primary intermediary hub, receiving gut-derived metabolites and inflammatory mediators through the portal circulation and thereby linking intestinal microbial signals to peripheral immune and metabolic responses. Collectively, these investigations emphasize the emerging mechanistic significance of microbiota-induced modulation of mitochondrial function in host defense mechanisms, thereby illuminating potential therapeutic approaches that focus on microbial composition, mitochondrial dynamics, and inflammasome signaling to alleviate infectious and inflammatory pathologies. This review integrates contemporary understandings of the interactions between microbiota, mitochondria, and NLRP3 inflammasome activation, thereby establishing a framework for prospective translational research.

Keywords:  NLRP3 inflammasome; host defense; infectious diseases; microbiome–mitochondria; mtDNA-mediated immunomodulation

DOI:  https://doi.org/10.3389/fcimb.2026.1866924
J Gerontol B Psychol Sci Soc Sci. 2026 Aug 27. pii: gbag180. [Epub ahead of print]

Early life predictors of subjective cognitive function in older age: Emerging longitudinal associations over six decades.

Gideon Neidenmark, Catherine Tuvblad, Jonas Persson.

   OBJECTIVES: Self-rated memory impairment is common in older age and has been related to objective cognitive decline and dementia. Recently, there has been growing interest in early-life predictors of late-life cognition, but research has been limited due to the absence of data spanning the entire lifespan. The present study investigated whether psychological health, social well-being, socioeconomic status (SES), and cognitive abilities at age 10 and 13 predicted subjective memory almost six decades later.
METHODS: Psychological health, social well-being, SES, and cognitive abilities were measured with standardized tests and questionnaires at age 10 and 13. Subjective memory, anxiety, and depressive symptoms were measured with the Prospective and Retrospective Memory Questionnaire (PRMQ) and Hospital Anxiety and Depression Scale (HADS) at age 67 (n = 625).
RESULTS: In a longitudinal autoregressive structural equation model (SEM), higher levels of psychological health at age 13 predicted lower levels of subjective memory at age 67. This association was independent of current anxiety and depressive symptoms. The model did not provide sufficient support that social well-being, SES, cognitive ability, and school performance at age 13 predicted subjective memory at age 67. Additional analysis revealed that psychological health at age 13, but not at age 10, and anxiety symptoms at age 67 uniquely predicted subjective memory at age 67.
DISCUSSION: These findings extend prior research by showing that psychological health is a robust predictor of subjective memory. Interventions targeting early-life psychological health may help identify individuals with different prospective cognitive outcomes in later life.

Keywords:  IDA-project; cognitive aging; life-course; metamemory; school anxiety

DOI:  https://doi.org/10.1093/geronb/gbag180
Curr Opin Pharmacol. 2026 Aug 27. pii: S1471-4892(26)00058-5. [Epub ahead of print]90 102662

Mitochondria as a therapeutic platform in inflammatory and degenerative disorders: mechanisms, biomarkers, and translational challenges.

Lamiaa M ElAbbasy.

Mitochondrial dysfunction has emerged as a convergent pathogenic mechanism across inflammatory and degenerative disorders, functioning not as a passive consequence but as an active amplifier of tissue injury, immune dysregulation, and impaired repair. Consistently observed mitochondrial abnormalities include excessive reactive oxygen species production, impaired oxidative phosphorylation, defective mitophagy, altered fission-fusion dynamics, and release of mitochondrial danger-associated molecular patterns, particularly cell-free mitochondrial DNA (cf-mtDNA), which serves both as a proinflammatory mediator and a potential circulating biomarker of disease activity. These alterations create self-reinforcing networks in which mitochondrial stress promotes innate immune activation, sustains inflammatory signaling, and accelerates structural or functional decline in vulnerable tissues. Mitochondria-targeted pharmacology has expanded rapidly, encompassing organelle-directed antioxidants, modulators of mitochondrial quality control, biogenesis or metabolic enhancers, nano-enabled delivery platforms, and emerging mitochondrial replacement strategies. Despite strong mechanistic appeal and encouraging preclinical data, clinical translation remains limited by the absence of validated pharmacodynamic biomarkers, an incomplete understanding of disease endotypes, inconsistent tissue target engagement, delivery barriers to mitochondria-rich compartments, and poor predictive value of animal models for human disease biology. The cf-mtDNA and related mitochondrial signatures are increasingly attracting attention for patient stratification, phenotyping, and therapeutic monitoring, although assay standardization remains unresolved. This review focuses on the core mechanisms that link mitochondrial dysfunction to disease progression. It also examines biomarker development and the major barriers to translation. Emerging approaches such as nanotechnology and mitochondrial replacement are discussed as supplementary strategies, not as the main focus of the review.

DOI: https://doi.org/10.1016/j.coph.2026.102662
J Physiol. 2026 Aug 28.

Adipose FGF21 signalling mediates the anti-senescence effects of protein restriction.

Xiaohan Yang, Yanni Wu, Yi Yang, Long Huang, Xianyang Jin, Xuemei Jiang, Chao Jin, Bin Feng, Lianqiang Che, Shengyu Xu, Yan Lin, Yong Zhuo, De Wu, Lun Hua.

  Dietary protein restriction (PR) is a well-recognized nutritional intervention that enhances metabolic health and extends lifespan. However, the mechanisms behind this phenomenon are not well understood. Here, using genetic loss-of-function models for fibroblast growth factor 21 (Fgf21) and its obligate co-receptor β-Klotho (Klb), we demonstrate that FGF21-KLB signalling in adipocytes is indispensable for the anti-senescence effects of PR. Specifically, adipocyte FGF21 signalling preserves mitochondrial integrity, maintains an anti-inflammatory milieu and sustains nicotinamide adenine dinucleotide (NAD+) homeostasis under PR. Mechanistically, FGF21 enhances adipocyte NAD+ abundance through activation of AMP-activated protein kinase to maintain mitochondrial integrity. Additionally, high-protein feeding induces adipocyte senescence and metabolic dysfunction could be mitigated by exogenous FGF21 supplementation. Together, these findings establish adipose FGF21 signalling as a pivotal endocrine axis that couples dietary protein availability to adipocyte NAD+ metabolism and identify it as a promising target for the prevention and treatment of age-related metabolic disorders. KEY POINTS: Dietary protein restriction improves metabolic health and extends lifespan, but the mechanisms responsible for these benefits are not fully understood. Fibroblast growth factor 21 (FGF21) is a hormone strongly induced by low-protein diets and has emerged as an important regulator of metabolic adaptation. We show that FGF21 signalling specifically in adipose tissue is essential for the anti-senescence effects of dietary protein restriction. FGF21 preserves mitochondrial integrity by maintaining nicotinamide adenine dinucleotide metabolism through AMP-activated protein kinase activation. Targeting the FGF21-adipose tissue pathway may provide new strategies to prevent or treat age-related metabolic dysfunction.

Keywords:  NAD+ homeostasis; fibroblast growth factor 21 (FGF21); mitochondrial integrity; protein restriction; white adipose tissue (WAT)

DOI:  https://doi.org/10.1113/JP291341
Mol Nutr Food Res. 2026 Sep;70(17): e70589

Dietary Intervention With Lutein, Docosahexaenoic Acid, and Choline During Early Development Improves Recognition Memory in Young Adult Females in an Experimental Model.

Leon Saschin, Gregor Fink, Maria Wohlfarth, Jonas Hauser, Jian Yan, Dirk Wiedermann, Mathias Hoehn, Jochen Wilhelm, Lea Quell, Elisabeth Sous, Jenny Voggel, Jörg Dötsch, Eva Nüsken, Kai-Dietrich Nüsken.

  The perinatal period and adolescence are critical for brain development, with nutrition being a crucial factor. Dietary intake of lutein, docosahexaenoic acid (DHA), and choline is positively associated with early neurodevelopment and cognitive function, but interactions remain unclear. This study systematically evaluates lutein, DHA, and choline to elucidate their specific and combined effects on neurodevelopment. To ensure fully controllable conditions, we performed nutritional interventions on a rat model during a critical developmental phase (days 14-56 after birth). After completion of the intervention, no relevant alterations in the open field test or the elevated zero maze were detected. However, both the combination of lutein, DHA, and choline and lutein monotherapy led to an increase in the recognition index for new objects in female rats. No relevant effects on blood and metabolic parameters were observed in any group. In vivo MRI analyses ruled out differences in brain morphology. Our results provide evidence that lutein supplementation during brain development has positive effects on recognition memory in female rats, underscoring the need for sex-specific research on nutritional strategies. Lutein supplementation, particularly in combination with DHA and choline, to enhance neurological development potential should be investigated in further translational studies.

Keywords:  antioxidants; developmental programming; lutein; memory; nutrition

DOI:  https://doi.org/10.1002/mnfr.70589
Front Nutr. 2026 ;13 1906996

Orally administered scallop-derived plasmalogens improve cognitive function in healthy middle-aged and older adults: a randomized, double-blind, placebo-controlled trial.

Mina Fukuchi, Mizuho Tanaka, Masafumi Nagata, Tsuyoshi Takara, Yasuhiro Sasuga.

   Background: Plasmalogens (Pls) are ether phospholipids enriched in the brain that help maintain synaptic integrity and support cognitive function. However, evidence of their cognitive benefits in otherwise healthy individuals remains limited. This randomized, double-blind, placebo-controlled trial examined whether supplementation with scallop-derived Pls (sPls) improves cognitive performance in cognitively healthy Japanese adults aged ≥40 years with below-average verbal memory at baseline.
Methods: Of 168 individuals screened, 68 eligible participants were randomly assigned (1:1) to receive either sPls (1 mg/day) or placebo for 12 weeks. Cognitive performance was assessed using the web-based Cognitrax battery (CNS Vital Signs), with the standardized verbal memory score as the primary outcome. Secondary outcomes included other cognitive domains and plasma brain-derived neurotrophic factor (BDNF) levels. Safety was evaluated through adverse event monitoring and clinical assessments.
Results: Sixty-six participants were included in the analysis. After 12 weeks, standardized verbal memory scores were significantly higher in the sPls group than in the placebo group (estimated marginal mean difference, 10.1; 95% confidence interval, 0.4-19.9; p = 0.042). The sPls group also showed significantly greater improvements in selected attention-related cognitive domains. Plasma BDNF levels increased in both groups, with no significant between-group differences; a modest negative correlation between BDNF levels and cognitive performance was observed in the sPls group at 12 weeks. No adverse events or clinically meaningful safety concerns were reported.
Conclusion: In cognitively healthy middle-aged and older adults with below-average verbal memory, 12 weeks of sPls supplementation was associated with improved verbal memory compared with placebo. Exploratory analyses also suggested potential improvements in selected attention-related cognitive domains. Dietary sPls may have the potential to support cognitive function in this population; however, further studies are required to confirm these findings and evaluate long-term safety.
Clinical trial registration: https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000066286, identifier UMIN000057985.

Keywords:  cognitive performance; dietary supplementation; plasmalogens; randomized controlled trial; scallop; verbal memory

DOI:  https://doi.org/10.3389/fnut.2026.1906996
Biochem Biophys Res Commun. 2026 Aug 21. pii: S0006-291X(26)01232-5. [Epub ahead of print]834 154468

Time-dependent and partially reversible mitochondrial remodeling induced by coenzyme Q10 depletion in HepG2 cells.

Ryo Takahashi, Mizuho Okamoto, Tsukika Tanaka, Tsubasa Asukabe, Yui Tomiyama, Rena Okuizumi, Michio Sato, Akio Fujisawa, Yorihiro Yamamoto, Misato Kashiba.

  Aging and age related pathological conditions are long-term processes in which cellular states gradually change over extended periods. However, many experimental studies of oxidative stress in cultured cells rely on short-term exposure to exogenous oxidative agents, which may not adequately reflect chronic oxidative conditions. To address this limitation, we established a cellular model of long-term oxidative stress by reducing endogenous antioxidant capacity through inhibition of coenzyme Q10 (CoQ10) biosynthesis rather than applying acute oxidative insults. Using HepG2 cells treated with 4-nitrobenzoic acid, we compared mitochondrial responses to acute and chronic CoQ10 depletion. CoQ10 levels were reduced under both acute and chronic conditions and were restored by co- treatment with 4-hydroxybenzoic acid. Acute CoQ10 depletion resulted in a reduced number of mitochondria and mitochondrial enlargement, accompanied by an increase in mitochondrial DNA copy number (mtDNAcn). In contrast, long-term culture under continuous CoQ10 depletion restored mitochondrial number, size, and mtDNAcn to levels comparable to those of control cells, despite persistently reduced CoQ10 content. However, cell proliferation remained impaired, and mitochondrial ultrastructural properties differed from those of control cells, indicating incomplete recovery under chronic conditions. Furthermore, 4-hydroxybenzoic acid reversed the mitochondrial alterations observed under acute conditions. Together, these findings demonstrate that mitochondrial responses to CoQ10 deficiency are strongly time dependent and involve reversible yet incomplete adaptive remodeling, highlighting the importance of modeling chronic oxidative stress when interpreting mitochondrial phenotypes.

Keywords:  Cell growth; CoQ10; Coenzyme Q10; Mitochondria; Mitochondrial DNA

DOI:  https://doi.org/10.1016/j.bbrc.2026.154468
Medicina (Kaunas). 2026 Aug 17. pii: 1574. [Epub ahead of print]62(8):

Vasomotor Symptoms and Their Association with Depressive and Anxiety Symptoms in Peri- and Postmenopausal Women: A Systematic Review of Observational Studies.

Oana Neda-Stepan, Virgil Radu Enătescu, Catalina Giurgi-Oncu, Elena Silvia Bernad, Radu Neamțu, Brenda-Cristiana Bernad, Alin Vasile Kadaș, Cristina Bredicean.

  Background and Objectives: Vasomotor symptoms (VMS), including hot flushes and night sweats, often co-occur with depressive and anxiety symptoms during the menopausal transition. This systematic review assessed the observational evidence for a quantitative association between VMS burden and affective symptoms in peri- and postmenopausal women. Materials and Methods: PubMed and PubMed Central were searched from database inception to 30 June 2025 for English-language, open-access observational studies reporting VMS and depressive and/or anxiety outcomes in peri- or postmenopausal women. Two reviewers independently screened records and full-text reports, and extracted data were independently verified. Study characteristics, symptom measures, prevalence or severity data, and quantitative association estimates were extracted. Owing to substantial heterogeneity of exposure and outcome measures, a structured narrative synthesis was conducted in accordance with the Synthesis Without Meta-analysis (SWiM) guideline. Risk of bias was appraised at item level using the Joanna Briggs Institute checklists and the Newcastle-Ottawa Scale, and the certainty of the evidence was rated using the GRADE approach. Results: Twelve studies involving approximately 9900 women from seven countries were included. In studies reporting adjusted estimates, greater VMS burden was associated with higher odds of depressive symptoms, with adjusted odds ratios ranging from 1.67 to 2.99; one longitudinal cohort reported an odds ratio of 2.95 for a worsening depressive-symptom trajectory. Evidence for anxiety was directionally concordant but considerably weaker: anxiety was assessed as a distinct outcome in only five of the 12 studies, none of which reported an adjusted effect estimate, and two of which were rated at high concern for risk of bias. Two studies were rated at overall low concern for risk of bias, seven at moderate concern, and three at high concern. Several studies suggested partial mediation through fatigue or poor sleep, whereas others supported direct or bidirectional associations. Conclusions: Greater VMS burden is consistently associated with depressive symptoms and, on a smaller and less certain evidence base, with anxiety symptoms. Certainty of the evidence was rated low for depression and very low for anxiety; the predominance of cross-sectional designs, the heterogeneity of instruments, largely unaddressed confounding, and the possibility of reverse causation preclude any causal inference. Women presenting with bothersome VMS may benefit from case-finding for mood and anxiety symptoms where a pathway to assessment and treatment exists, and prospective studies should test whether VMS-directed interventions improve affective outcomes.

Keywords:  anxiety; depression; hot flashes; menopause; night sweats; perimenopause; systematic review; vasomotor symptoms; women’s mental health

DOI:  https://doi.org/10.3390/medicina62081574
Nutrients. 2026 Aug 21. pii: 2739. [Epub ahead of print]18(16):

Impact of N-PEP-12 Supplementation on Attentional Performance and Mental Wellbeing in Healthy Adults with Subjective Cognitive Complaints: A Randomized, Placebo-Controlled Trial.

Diana Chira, Nicoleta Jemna, Olivia Verișezan-Roșu, Ana-Maria Buruiană, Ștefan Strilciuc, Vlad-Florin Chelaru, Simona Pârvu, Dafin Fior Mureșanu.

  Background: Subjective cognitive complaints (SCCs) are common in middle-aged and older adults and may reflect early cognitive changes, alongside alterations in stress, mood, sleep, and quality of life. N-PEP-12 is a peptide-based nutritional supplement with potential neuroprotective effects, but evidence of its benefits in healthy adults with SCCs remains limited. Objective: To evaluate the effects of N-PEP-12 supplementation on attention, cognitive function, and mental wellbeing in healthy middle-aged and older adults with SCCs. Methods: In this prospective, randomized, double-blind, placebo-controlled trial, 276 participants aged 50-75 years with SCCs and no clinically significant cognitive impairment were randomized to placebo, N-PEP-12 45 mg, or N-PEP-12 90 mg. Assessments were performed at baseline and after 30, 90, and 180 days. Primary outcomes included Test of Attentional Performance measures. Secondary outcomes included WAIS-IV Digit Span Forward and Backward, perceived stress, mood, sleep quality, and EQ-5D-5L visual analog scale. Results: Across the three primary attention outcomes analyzed jointly in a multivariate repeated-measures model, there was a significant group-by-visit interaction (p = 0.003) and a significant effect of visit (p < 0.001), without a significant main effect of treatment arm (p = 0.133), indicating a time-dependent treatment effect. This result was obtained in a sensitivity analysis population in which missing values were imputed under assumptions least favorable to the active arms. In exploratory endpoint-specific comparisons at 90 days, both N-PEP-12 groups showed greater improvements than placebo in alertness, attention omissions and memory omissions, and Digit Span Forward and Backward scores also improved. In a subsequent uncontrolled extension phase, in which all participants received active treatment, participants initially assigned to placebo showed comparable improvements after switching to N-PEP-12 90 mg. These observations are exploratory. Adverse events were infrequent and similarly distributed across groups. Conclusions: N-PEP-12 supplementation was associated with improvements in attention, working memory, and mental wellbeing in healthy middle-aged and older adults with subjective cognitive complaints. These findings support further investigation of N-PEP-12 as a nutritional intervention for early subjective cognitive changes associated with aging.

Keywords:  N-PEP-12; attention; memory; mental wellbeing; subjective cognitive complaints

DOI:  https://doi.org/10.3390/nu18162739
Front Endocrinol (Lausanne). 2026 ;17 1894588

The multisystem impact of perimenopausal hormonal fluctuations on chronic disease risk.

Lijia Luo, Lei Li, Xi Wang, Wenpei Bai.

  Hormonal shifts during menopause are crucial to women's health, characterized by a reduction in estrogen levels and an elevation in circulating androgen, which may result from either natural or surgical menopause. This review synthesizes current knowledge on the multifaceted mechanisms by which menopausal hormonal fluctuations reshape systemic health span. This review synthesizes current knowledge of the complex mechanisms between hormonal changes and immune cell interactions, highlighting how these relationships can influence disease risk during the menopausal transition. We also emphasize how these neuroendocrine-immune-microbial disruptions facilitate the pathogenesis of neurodegenerative disorders, cardiovascular diseases, osteoporosis and the evolution of tumorigenic microenvironments. Finally, we discuss key challenges and future research directions in related research with goal of informing novel strategies to prevent and treat menopause-related diseases.

Keywords:  aging; estrogen; immunity; menopause; women

DOI:  https://doi.org/10.3389/fendo.2026.1894588
Front Aging Neurosci. 2026 ;18 1878831

Potential effects of β-hydroxy-β-methylbutyrate and exercise on brain aging and age-related disorders: implications for immunometabolic regulation and muscle-brain-immune crosstalk.

Boyuan Shi, Zheng Han.

  β-Hydroxy-β-methylbutyrate (HMB), a bioactive leucine metabolite, has emerged as a potentially valuable nutritional compound with effects extending beyond skeletal muscle metabolism toward systemic immunometabolic regulation. This review summarizes evidence from 24 experimental and clinical studies regarding the potential relevance of HMB to brain aging and age-related disorders, with emphasis on mitochondrial regulation, inflammatory signaling, redox homeostasis, and exercise-associated adaptations. Most studies report improvements in muscle strength, physical performance, and functional capacity, frequently without substantial increases in muscle mass. Proposed mechanisms include modulation of protein turnover, attenuation of apoptosis, regulation of autophagy, and preservation of mitochondrial dynamics. Emerging evidence also suggests that HMB may influence inflammatory gene expression, oxidative stress pathways, and immune-related signaling. However, direct central nervous system (CNS)-specific evidence remains limited, as most available findings derive from peripheral, preclinical, or exercise-associated models. Importantly, many included studies employed multicomponent interventions involving resistance training, creatine, vitamin D, or combined nutritional supplementation, making it difficult to isolate HMB-specific effects. Exercise itself appears to remain the principal driver of mitochondrial adaptation, inflammatory modulation, and functional improvement, whereas HMB demonstrates primarily adjunctive or context-dependent effects. Consequently, HMB should presently be regarded as a potential indirect modulator of muscle-brain-immune interactions during aging rather than a definitively established neuroactive compound. Further mechanistically rigorous and CNS-focused studies are required.

Keywords:  aging; brain–muscle–immune axis; endurance performance; molecular neurobiology; neuropsychiatric disorders; β-hydroxy-β-methylbutyrate

DOI:  https://doi.org/10.3389/fnagi.2026.1878831
Front Cell Dev Biol. 2026 ;14 1866640

Mitochondrial regulation of cellular senescence heterogeneity.

Minseo Ahn, Sung-Jin Yoon, Jae Ho Seo.

  Cellular senescence is a stable cell-cycle arrest program accompanied by extensive metabolic remodeling and acquisition of a senescence-associated secretory phenotype (SASP). Emerging evidence indicates that senescence is not a uniform endpoint but a heterogeneous spectrum of cell states shaped by the nature of the initiating stimulus. Mitochondria have recently emerged as central regulators of this heterogeneity by integrating metabolic, redox, and inflammatory signaling. Senescent cells share common mitochondrial features-including increased mitochondrial mass, elevated reactive oxygen species (ROS), impaired mitophagy, and altered metabolic programs-yet distinct senescence subtypes exhibit unique mitochondrial adaptations. Replicative senescence is governed by a telomere-mitochondria feedback loop, whereas stress- and oncogene-induced senescence involve rapid mitochondrial stress responses and stimulus-specific metabolic rewiring. Therapy-induced senescence further introduces context-dependent mitochondrial dependencies that influence therapeutic resistance and senolytic vulnerability. In this review, we synthesize current understanding of mitochondrial regulation across senescence subtypes and highlight how mitochondrial dysfunction actively drives senescence heterogeneity. We further discuss emerging therapeutic strategies that exploit mitochondrial vulnerabilities to selectively modulate or eliminate senescent cells. Understanding mitochondrial control of senescence heterogeneity provides a conceptual framework for developing precision interventions in aging and cancer.

Keywords:  cellular senescence; metabolic reprogramming; mitochondrial dysfunction; mitophagy; reactive oxygen species (ROS); senescence heterogeneity; senescence-associated secretory phenotype (SASP); senolytics

DOI:  https://doi.org/10.3389/fcell.2026.1866640
Nutr Neurosci. 2026 Aug 26. 1-23

Erucic acid arbitrates neuroprotection in streptozotocin-induced memory deficit via improving oxidative stress/neuroinflammatory indicators/cholinergic activity in rodents.

Nadeem Sayyed, Muhammad Afzal, Misbahuddin Rafeeq, Asma B Omer, Fahad A Al-Abbasi, Shakilur Rahman, Mohammed Al-Zharani, Sami I Alzarea, Imran Kazmi.

   BACKGROUND: Erucic acid (EA), a monounsaturated omega-9 fatty acid derived from Raphanus sativus L. seeds, has antioxidant and anti-inflammatory properties. This study investigated its neuroprotective effects against streptozotocin (STZ)-induced diabetes-associated cognitive dysfunction in rats.
METHODS: Male Wistar rats were randomly assigned to five groups: normal control, STZ control (60 mg/kg), STZ + EA (10 mg/kg), STZ + EA (20 mg/kg), and EA (20 mg/kg) per se. EA was administered orally for 38 days. Blood glucose and body weight were measured before STZ administration and at the end of the study. Cognitive function was assessed using the Y-maze and Morris water maze (MWM). Cholinergic function, oxidative stress, neurotransmitters, inflammatory mediators, apoptosis, and cellular energy status were evaluated biochemically, and hippocampal histopathology was performed.
RESULTS: EA treatment significantly reduced hyperglycemia and attenuated diabetes-induced body weight loss. EA improved spontaneous alternation in the Y-maze and spatial learning and memory in the MWM, reducing escape latency and increasing target-quadrant time. EA decreased acetylcholinesterase activity while increasing choline acetyltransferase activity, restored antioxidant defenses, and reduced MDA, ROS, and NO levels. It also normalized neurotransmitter levels, suppressed TNF-α, IL-1β, IL-6, NF-κB, and caspase-3, increased IL-10, and improved the ATP/ADP ratio. Histopathology demonstrated preservation of hippocampal neuronal architecture.
CONCLUSIONS: EA ameliorated diabetes-associated cognitive dysfunction by improving learning and memory, preserving cholinergic neurotransmission, reducing oxidative stress and neuroinflammation, inhibiting neuronal apoptosis, and restoring cellular energy metabolism. These findings support the therapeutic potential of EA for managing cognitive impairment associated with diabetes.

Keywords:  Acetylcholinesterase; Alzheimer's disease; cognitive dysfunction; diabetes; erucic acid; neuroprotection; oxidative stress; streptozotocin

DOI:  https://doi.org/10.1080/1028415X.2026.2718394
Biomolecules. 2026 Aug 17. pii: 1197. [Epub ahead of print]16(8):

Pyrroloquinoline Quinone (PQQ) as a Mitochondrial Rejuvenation Strategy in Aesthetic Dermatology: Mechanisms, Therapeutic Potential, and Future Clinical Applications.

Kyu-Ho Yi.

   BACKGROUND: Mitochondrial dysfunction is increasingly recognized as a central contributor to intrinsic skin aging, photoaging, cellular senescence, impaired extracellular-matrix homeostasis, dysregulated pigmentation, and delayed recovery after energy-based or minimally invasive procedures. Pyrroloquinoline quinone (PQQ) is a redox-active ortho-quinone that has attracted interest because it can participate in repeated redox cycling, protect mitochondrial function, and activate signaling associated with mitochondrial biogenesis.
OBJECTIVE: This narrative review evaluates the mechanistic basis, available dermatologic evidence, translational opportunities, and major uncertainties surrounding PQQ as a mitochondrial rejuvenation strategy in aesthetic dermatology.
METHODS: PubMed/MEDLINE and Europe PMC were searched from database inception through 10 August 2026 using PQQ-, mitochondrial-, skin-, delivery-, and safety-related terms; reference lists were also screened. Mechanistic, preclinical, skin-focused, human, and regulatory evidence was synthesized narratively.
RESULTS: Experimental studies support PQQ-mediated activation of mitochondrial biogenesis pathways and protection against oxidative injury in several cell and animal systems. Skin-specific evidence includes attenuation of oxidative stress, DNA damage, senescence markers, and matrix metalloproteinases in accelerated-aging mouse models; protection of UVA-exposed human dermal fibroblasts; suppression of UVB-induced caspase-1 release in keratinocytes; a small oral dry-skin study; and a multi-ingredient topical study containing an allyl PQQ derivative. These studies do not establish PQQ-specific clinical aesthetic efficacy.
CONCLUSION: PQQ is a biologically plausible mitochondrial-support compound, but it should currently be regarded as an investigational ingredient rather than an established aesthetic treatment. Carefully designed formulation, toxicology, dose-finding, biomarker, and randomized clinical studies are required before claims regarding wrinkle reduction, pigment improvement, enhanced collagen production, or accelerated post-procedure recovery can be justified.

Keywords:  PQQ; aesthetic dermatology; cellular senescence; mitochondria; oxidative stress; photoaging; pyrroloquinoline quinone; skin aging

DOI:  https://doi.org/10.3390/biom16081197