bims-mistre 2026-07-19 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–07–19
eighteen papers selected by
Ellen Siobhan Mitchell, MitoQ

Impaired Renal Mitochondria and Bioenergetics During Obesity-Associated NAFLD.
More gas, fewer brakes: Mitochondria withhold CoQ at the cost of ferroptosis defense.
Mitochondrial Dysfunction in Ulcerative Colitis: Pathogenic Mechanisms and Novel Therapeutics.
Blockade of the GDF15/GFRAL Axis: Translational Advances in Cachexia, Immune Suppression, and Beyond.
ROS-driven mitochondrial and mtDNA release as a novel pathway of metabolic injury in diabetes.
Acute mitochondrial dysfunction impairs neuromuscular transmission and contractility in mouse diaphragm: the protective potential of 25-hydroxycholesterol.
Salidroside alleviates age-related metaphase II oocyte aging by enhancing mitochondrial complex I-mediated oxidative phosphorylation.
Coffee as a polypharmacological modulator of mitochondrial health: from molecular mechanisms to translational implications.
Stress Induced Mitochondrial Hyperfusion (SIMH): A Concise Review on SIMH in Neurodegenerative Disorders and Other Diseases.
The SIRT5-SUCLG2 desuccinylation axis delays ovarian aging via a mitochondrial-epigenetic regulatory mechanism.
Therapeutic targeting of mitochondrial dysfunction in heart failure: a systematic review & meta-analysis of clinical outcomes.
Dose and sex-specificity in Canagliflozin-mediated neuroprotection in aging mice.
The mitochondrial logic of inflammaging: how energy imbalance drives fibroblast SASP and tissue-specific aging.
Is Urolithin A(UA) a Pharmacologically Credible Neuro-Nutraceutical? A Critical Review of Mechanisms, Brain Exposure, and Evidence Gaps in Alzheimer's and Parkinson's Disease.
Ergothioneine attenuates age-related declines in circadian rhythmicity.
Association between GDF-15 and sarcopenia progression in older adults: results from a population-based study.
Impaired mitochondrial flexibility hinders fat pad remodeling in obese mice after 24 h of fasting.
Standardized Saffron Extract Formulation for Low Mood and Subclinical Depressive Symptoms: A Randomized, Double-Blind, Placebo-Controlled Trial.

Nutrients. 2026 Jun 24. pii: 2061. [Epub ahead of print]18(13):

Impaired Renal Mitochondria and Bioenergetics During Obesity-Associated NAFLD.

Amod Sharma, Reza Hakkak, Shannon Rose, Neriman Gokden, Nirmala Parajuli.

  Background/Objectives: Obesity-associated non-alcoholic fatty liver disease (NAFLD) drives systemic metabolic stress and accelerates chronic kidney disease, yet the mechanistic links remain unclear. Mitochondrial dysfunction has emerged as a central mediator of obesity-induced organ injury. Here, we investigated renal mitochondrial remodeling in a rat model of obesity-associated NAFLD (Ob-NAFLD) and examined the effects of metformin. Methods: Female Zucker rats (obese fa/fa and lean Fa/Fa) were fed an AIN-93G diet for eight weeks, followed by 10 weeks of metformin treatment in designated groups. Kidney tissues were analyzed using biochemical assays, immunoblotting, blue native PAGE, in-gel activity assays, and histological evaluation. Results: In Ob-NAFLD rats, renal ATP levels were elevated despite reduced electron transport chain (ETC) Complex III and increased Complex V expression, reflecting compensatory ATP synthase hyperactivity uncoupled from efficient oxidative phosphorylation. Mitochondrial dynamics were disrupted such that inhibitory phosphorylation of DRP1 was reduced, promoting fission, and total OPA1 expression was decreased with a shift in short-to-long isoform balance, indicating impaired fusion and cristae remodeling. Notably, ATPase inhibitory factor 1 (IF1), a checkpoint that limits ATP synthase overdrive, remained stably expressed, suggesting an adaptive ceiling or failed protective control under chronic metabolic stress. Metformin partially alleviated bioenergetic stress by lowering ATP and modestly restoring Complex III, yet ETC imbalance and structural remodeling persisted, revealing the limitations of metabolic modulation alone. Conclusions: These findings position entrenched mitochondrial dysregulation as a mechanistic bridge linking obesity-driven liver disease to kidney injury. Therapeutic strategies combining metabolic interventions with targeted restoration of ETC coordination, mitochondrial dynamics, and regulatory checkpoints such as IF1 may be required to fully restore renal mitochondrial health and prevent the progression of metabolic kidney disease.

Keywords:  ATP; kidney injury; metformin; mitochondrial dynamics; obesity–NAFLD

DOI:  https://doi.org/10.3390/nu18132061
J Cell Biol. 2026 Aug 03. pii: e202606160. [Epub ahead of print]225(8):

More gas, fewer brakes: Mitochondria withhold CoQ at the cost of ferroptosis defense.

Mami Sato, Florencio Porto Freitas, José Pedro Friedmann Angeli.

Coenzyme Q (CoQ or ubiquinone) is an essential cofactor for mitochondrial energy production and a vital radical-trapping antioxidant that maintains membrane integrity. Additionally, CoQ shares an early biosynthetic pathway with cholesterol biosynthesis. In this issue, Ndoci et al. (https://doi.org/10.1083/jcb.202507174) reveal a regulatory system that preserves mitochondrial CoQ levels when the mevalonate pathway is impaired, though this prioritization leaves cells vulnerable to oxidative stress.

DOI: https://doi.org/10.1083/jcb.202606160
J Biochem Mol Toxicol. 2026 Jul;40(7): e71021

Mitochondrial Dysfunction in Ulcerative Colitis: Pathogenic Mechanisms and Novel Therapeutics.

Hongyan Ran, Siyuan Zhou, Hui Zou, Juan Deng, Fei Yin.

  Ulcerative colitis (UC) is a chronic inflammatory bowel disease driven by a complex interplay of mitochondrial dysfunction. These defects impair energy production, increases oxidative stress, and disrupts immune balance. Here we review three therapeutic classes that target mitochondrial pathways: antioxidants, metabolic modulators, and microbiota-directed strategies. In UC, mitochondrial dysfunction creates a self-perpetuating cycle through metabolic-immune crosstalk, the leakage of mitochondrial DNA, and the redistribution of cardiolipin. Moreover, the gut microbiota and mitochondria engage in bidirectional crosstalk that amplifies intestinal inflammation. Encouragingly, agents that restore mitochondrial function have shown therapeutic benefit in preclinical and early clinical studies. Notable examples include the mitochondria-targeted antioxidant MitoQ (currently in a Phase 2b trial for UC), ClpP (caseinolytic protease P) activators that reprogram T-cell metabolism, and engineered probiotics that deplete pro-inflammatory succinate. This review synthesizes current evidence on mitochondrial dysfunction in UC, bridging molecular mechanisms, immune-metabolic interactions, and emerging therapeutics to propose a new treatment paradigm centered on mitochondrial restoration.

Keywords:  inflammation; metabolic reprogramming; mitochondrial dysfunction; oxidative stress; ulcerative colitis (UC)

DOI:  https://doi.org/10.1002/jbt.71021
Curr Drug Targets. 2026 Jul 07.

Blockade of the GDF15/GFRAL Axis: Translational Advances in Cachexia, Immune Suppression, and Beyond.

Qi Zhou, Yan Yang.

   INTRODUCTION: Growth differentiation factor 15 (GDF15) is an endocrine hormone belonging to the transforming growth factor β (TGF-β) superfamily. In normal physiology, GDF15 is expressed in multiple tissues at low concentrations. However, its expression significantly increases following many pathological conditions, such as tissue injury, inflammation, mitochondrial dysfunction, and cancer. GDF15 has emerged as a significant biomarker and a promising therapeutic target since the identification of its central nervous system-restricted receptor, Glial cell line-derived neurotrophic factor family receptor α-like (GFRAL)-REarranged during Transfection proto-oncogene (RET).
METHODS: We conducted a narrative review of the published literature on the molecular mechanisms of GDF15, with special focus on interventional studies using anti-GDF15 drugs. This review highlights the therapeutic potential of blockade of the GDF15/GFRAL axis based on current preclinical and clinical data.
RESULTS: GDF15 is a multifaceted factor that exerts a central role in regulating energy balance, demonstrating context-dependent effects. It acts as a key mediator of anorexia and weight loss in cancer cachexia. Furthermore, GDF15 contributes to the remodeling of the tumor immune microenvironment by inhibiting immune cell functions. Therapeutic strategies developed based on this, such as GDF15 antagonists, neutralizing antibodies, GFRAL receptor fusion proteins, as well as the combined application of GDF15-targeted drugs and immune checkpoint inhibitors, have yielded promising results in clinical trials. We also include a discussion of the potential limitations in the development of anti-GDF15 drugs.
DISCUSSION: GDF15-targeted drugs have shown potential benefits in reversing cancer cachexia and may enhance anti-tumor immunity, but this remains to be confirmed in larger, controlled studies. The primary challenge in targeting GDF15 lies in the complexity and context-dependent nature of its biological functions.
CONCLUSION: GDF15 represents a highly compelling therapeutic target for metabolic and oncological diseases. Overcoming the challenges posed by its biological complexity is essential to successfully translating GDF15-targeted strategies into precision medicine applications.

Keywords:  GDF15 receptor; Growth differentiation factor-15 (GDF-15); glial-derived neurotro

DOI:  https://doi.org/10.2174/0113894501465574260629112344
J Mol Endocrinol. 2026 Jul 15. pii: JME-25-0203. [Epub ahead of print]

ROS-driven mitochondrial and mtDNA release as a novel pathway of metabolic injury in diabetes.

Dandan Chen, Yuxin Jia, Xiaohong Duan, Jianhua Huang, Xiaohong Deng.

  Mitochondrial dysfunction driven by chronic hyperglycemia is a hallmark of diabetes, yet how this metabolic stress communicates pathological signals beyond individual cells remains poorly understood. In this study, we identified a novel mechanism linking chronic hyperglycemia to systemic metabolic impairment through ROS-mediated extracellular release of structurally intact mitochondria and mitochondrial DNA (mtDNA). In HepG2 cells exposed to high glucose (HG), extracellular release of structurally intact mitochondria was visualized by co-staining of mitochondria and the plasma membrane, together with electron microscopy. Mitochondria-enriched fractions isolated from culture supernatants were further quantified using flow cytometry and qPCR. Cell-free mtDNA (cf-mtDNA) was visualized with co-staining of mitochondria and double- stranded DNA, isolated through differential centrifugation and ultrafiltration, and quantified by qPCR. We demonstrate that HG stimulates the release of exosome-enclosed mtDNA as well as fragmented cf-mtDNA. Concurrently, HG induces mitochondrial dysfunction and markedly increases mitochondrial ROS (mtROS). Treatment with MitoTEMPO, a mitochondria-targeted ROS scavenger, significantly reduced HG-induced extracellular release of mitochondria and mtDNA, supporting the ROS dependence of this process. In diabetic mice, we detected elevated circulating mtDNA copy number and pronounced mitochondrial dysfunction in liver and muscle, including reduced ATP production, mitochondrial swelling, cristae disruption, and elevated MDA levels. Resting metabolic rate was markedly decreased, indicating impaired systemic respiratory metabolism. Serum analyses revealed increased 8-OHdG, pyruvic acid, GDF-15, and FGF-21, along with reduced FT3, reflecting severe oxidative stress and mtDNA damage. These findings uncover a novel mechanism in which hyperglycemia-induced ROS drive mitochondrial extrusion, potentially linking metabolic stress to systemic metabolic deterioration.

Keywords:  Diabetes mellitus; ROS; mitochondrial release; resting metabolic rate

DOI:  https://doi.org/10.1530/JME-25-0203
J Physiol Biochem. 2026 Jul 16. pii: 68. [Epub ahead of print]82(1):

Acute mitochondrial dysfunction impairs neuromuscular transmission and contractility in mouse diaphragm: the protective potential of 25-hydroxycholesterol.

Eva A Kapliukhina, Nikita S Fedorov, Andrei N Tsentsevitsky, Vadim V Salnikov, Anastasia A Ponomareva, Guzel F Zakyrjanova, Artem I Malomouzh, Alexey M Petrov.

  Mitochondrial impairment, accompanied by excessive reactive oxygen species (ROS) production, is a key contributor to muscle atrophy and neuromuscular disorders, leading to locomotor and respiratory failure. Antimycin A (AA), an inhibitor of the electron transport chain complex III, is an effective tool to mimic mitochondrial dysfunction, whereas 25-hydroxycholesterol (25-HC) is an immune-related oxysterol that can modulate neuromuscular activity via the membrane estrogen receptor α (ERα)/inositol triphosphate receptor/cytoplasmic Ca2+ axis. Herein, we investigated the effects of AA treatment in mouse diaphragm nerve-muscle preparations and tested the hypothesis that 25-HC can mitigate AA-induced mitochondrial damage. AA increased mitochondrial ROS production and reduced mitochondrial Ca2+ levels and membrane potential. This was accompanied by an elevation of extracellular H2O2 levels and lipid peroxidation, as well as a decline in both muscle fiber contractility and evoked exocytosis at the neuromuscular junction (NMJ). Furthermore, alterations were observed in the shape of miniature end-plate responses to the release of single neurotransmitter quanta. 25-HC, at a submicromolar concentration, inhibited AA-induced mitochondrial dysfunction and oxidative stress. Additionally, 25-HC alleviated AA-dependent functional NMJ disturbances but did not reverse the muscle fiber contraction deficit. The ability of 25-HC to decrease AA-driven mitochondrial ROS generation was blocked by a selective ERα antagonist and by chelation of cytoplasmic Ca2+. Thus, AA induces mitochondrial damage accompanied by oxidative stress, contractile and NMJ impairments. 25-HC can counteract AA-mediated mitochondrial dysfunction and partially restore NMJ function.

Keywords:  25-hydroxycholesterol; Antimycin A; Calcium; Mitochondrial dysfunction; Neuromuscular junction; Skeletal muscle

DOI:  https://doi.org/10.1007/s13105-026-01211-0
Cell Signal. 2026 Jul 11. pii: S0898-6568(26)00389-X. [Epub ahead of print]147 112732

Salidroside alleviates age-related metaphase II oocyte aging by enhancing mitochondrial complex I-mediated oxidative phosphorylation.

Feimiao Wang, Zhaoyang Wang, Jialing Li, Yanjie Hao, Lu Wang, Jinfang Wang, Rong Hu, Fang Xu.

  The deterioration of metaphase II (MII) oocyte quality is a principal factor compromising fertility in women of advanced maternal age and a core hallmark of ovarian aging; however, effective interventions to counteract this age-related decline are currently lacking. Although salidroside (Sal) exhibits health-promoting and anti-aging properties, its protective effects against MII oocyte aging and the underlying mechanisms remain poorly understood. In this study, we demonstrated that salidroside supplementation significantly improved multiple aspects of MII oocyte quality, particularly oocyte maturation and developmental competence. Comprehensive transcriptomic analysis revealed that salidroside rescues aged oocyte quality primarily by enhancing oxidative phosphorylation (OXPHOS). This enhancement effectively reduced reactive oxygen species (ROS) accumulation, thereby attenuating DNA damage and apoptosis. Furthermore, we identified that differentially expressed genes in the OXPHOS pathway were predominantly enriched in the subunits of mitochondrial respiratory chain complex I. The protective effects of salidroside in aged MII oocytes were markedly abolished by rotenone, indicating that salidroside primarily exerts its beneficial effects through mitochondrial complex I-mediated OXPHOS. Together, our findings highlight salidroside supplementation as a promising therapeutic strategy to ameliorate age-related MII oocyte deterioration, delay ovarian aging and improve reproductive outcomes. Future studies should focus on the translational potential of this intervention for human clinical applications.

Keywords:  Aging; Mitochondrial complex I; Oocyte; Oxidative phosphorylation; Salidroside

DOI:  https://doi.org/10.1016/j.cellsig.2026.112732
J Transl Med. 2026 Jul 17.

Coffee as a polypharmacological modulator of mitochondrial health: from molecular mechanisms to translational implications.

Zhaochang Jiang, Yu Ding.

   BACKGROUND: Coffee is one of the most widely consumed beverages worldwide, yet its biological effects have often been attributed primarily to caffeine. Emerging evidence suggests that coffee contains a complex array of bioactive compounds, including chlorogenic acids, trigonelline, diterpenes, and melanoidins that collectively exert pleiotropic effects on cellular metabolism. However, a comprehensive framework linking the full spectrum of coffee-derived bioactives to mitochondrial health and chronic disease prevention is still lacking.
MAIN BODY: This review proposes an integrated perspective on coffee as a systemic "mitochondrial network optimizer." We present this model as an integrative framework and hypothesis rather than an established causal model. We synthesize molecular, pre-clinical, and clinical evidence suggesting that coffee bioactives converge on key regulatory nodes, namely the AMPK/SIRT1/PGC-1α axis, Nrf2/ARE antioxidant pathway, PINK1/Parkin-mediated mitophagy, and mitochondrial calcium signaling to coordinately enhance mitochondrial biogenesis, quality control, redox defense, and metabolic efficiency. These multi-targeted mechanisms provide a plausible biological basis for the consistent epidemiological associations between moderate coffee consumption and reduced risk of metabolic diseases (type 2 diabetes, non-alcoholic fatty liver disease), neurodegenerative disorders (Parkinson's, Alzheimer's), and cardiovascular conditions. Furthermore, we critically examine key determinants of response heterogeneity, including non-linear hormetic dose-response relationships, inter-individual variability (CYP1A2 genotype, gut microbiota, sex), and the impact of coffee processing and brewing methods on bioactive composition.
CONCLUSIONS: Collectively, these findings support the hypothesis that coffee may serve as a paradigm of polypharmacological dietary intervention that targets fundamental pathways of mitochondrial resilience. Moving beyond reductionist views centered on single compounds, we propose that the holistic effects of coffee are best understood through systems-level modulation of mitochondrial homeostasis. Future research should prioritize precision nutrition approaches stratified by genotype, microbiome, and metabolic phenotype, to translate these mechanistic insights into personalized dietary recommendations and the development of mitochondria-targeted nutraceuticals. We caution that this integrative framework requires direct validation in human causal studies.

Keywords:  Coffee; Hormesis; Mitochondrial biogenesis; Oxidative stress; Precision nutrition

DOI:  https://doi.org/10.1186/s12967-026-08662-5
Organelle. 2025 ;3

Stress Induced Mitochondrial Hyperfusion (SIMH): A Concise Review on SIMH in Neurodegenerative Disorders and Other Diseases.

Jeffrey D Brown, Mei-Zhen Cui, Xuemin Xu.

  Mitochondria are critical for cell health, and damaged or dysfunctional mitochondria have been strongly linked to various human diseases, particularly neurodegenerative disorders. Mitochondrial function is regulated by several mechanisms, including the regulation of mitochondrial shape, size, number, and morphology. Mitochondria constantly fuse together and separate; this fusion and fission process is known as mitochondrial dynamics. These mitochondrial dynamics are modulated in response to various stimuli, and recent reports have demonstrated that mitochondria undergo hyperfusion under mild to moderate stress conditions, resulting in the formation of elongated filaments. This phenomenon is referred to as stress induced mitochondrial hyperfusion (SIMH). SIMH is associated with enhanced protection of mitochondria and improved cell viability under stress conditions. The induction of hyperfusion can be triggered by diverse stressors, each with distinct and unique mechanisms. This mini review will focus on these stressors and their corresponding mechanisms, as well as the subsequent effects on mitochondrial and cell health. Additionally, disease models which demonstrate a correlation between specific disease-related stress conditions and mitochondrial hyperfusion are discussed.

Keywords:  Drp1; ER Stress; MAM; Mfn; Mitochondrial dynamics; Neurodegenerative disorders; OPA1; SIMH; UPR

DOI:  https://doi.org/10.61747/0ifp.202503002
Nat Commun. 2026 Jul 15.

The SIRT5-SUCLG2 desuccinylation axis delays ovarian aging via a mitochondrial-epigenetic regulatory mechanism.

Dejun Xu, Shuaifei Song, Qingmiao Shi, Zhiling Zhao, Wenhao Zhao, Lei Wang, Guangxin E, Yanguo Han, Yongju Zhao, Zhongquan Zhao.

Mitochondrial dysfunction and epigenetic alterations play critical roles in aging-related diseases, yet the molecular mechanisms linking mito-nuclear crosstalk to ovarian aging remain poorly understood. Here, single-cell transcriptome analysis of aging ovaries revealed senescence-associated hallmark alterations, including abnormally elevated mitochondrial metabolism, disrupted histone modification patterns, and enrichment of the senescence-associated secretory phenotype (SASP). We demonstrated that impaired SIRT5-mediated desuccinylation constitutes a key driver of ovarian aging. Mechanistically, we identified succinyl-coenzyme A (CoA) synthetase GDP-forming subunit β (SUCLG2) in the tricarboxylic acid (TCA) cycle as the main target of SIRT5-mediated desuccinylation. SUCLG2 desuccinylation at lysine residues K93 and K101 enhanced its protein stability and activity, thereby improving mitochondrial function upon cellular senescence. However, SUCLG2 hypersuccinylation specifically increased H4K8ac through acetyl-CoA accumulation in nucleus, leading to the overexpression of metabolism-related genes to compensate for the energy demand deficiency caused by decreased mitochondrial function during cellular senescence. In vivo functional studies demonstrated that acetyl-CoA oversupply accelerated ovarian aging, whereas ovarian gene therapy employing a SUCLG2 desuccinylation mutant ameliorated this condition. This study illuminates the molecular mechanisms underlying ovarian aging and identifies the SIRT5-SUCLG2 axis as a promising therapeutic target for age-related ovarian dysfunction.

DOI: https://doi.org/10.1038/s41467-026-75502-x
Front Cardiovasc Med. 2026 ;13 1824101

Therapeutic targeting of mitochondrial dysfunction in heart failure: a systematic review & meta-analysis of clinical outcomes.

Omer Mohammed, Shabrin Abdul Rasheed, Ananya Arora, Sharon Velamparambil Sunny, Afthab Salam Kanniyan, Shilla Thomas, Basil Wahid Bhat, Venu Pararath Gopalakrishnan, Jeffrey George, Akiva Rosenzveig, Aravinda Nanjundappa, Shelby Kutty.

   Introduction: Mitochondrial dysfunction is recognised as a key driver of heart failure (HF) pathophysiology, contributing to oxidative stress, apoptosis, and impaired energy production in cardiomyocytes. Although therapeutic agents aimed at restoring mitochondrial function have demonstrated promise in animal models and early-phase clinical trials, their efficacy in clinical practice remains uncertain. This meta-analysis evaluated the impact of these agents on clinical outcomes in HF patients.
Methods: A systematic literature search was conducted across PubMed, Cochrane Library, ScienceDirect, Google Scholar, and ClinicalTrials.gov for studies published through May 2025. Thirty one studies (24 RCTs and 7 crossover trials) were included in meta-analysis. Standardized mean difference was pooled for changes in left ventricular ejection fraction (LVEF), NYHA class and six-minute walk test (6MWT) distance compared to baseline, and risk ratios (RR) were pooled for heart failure-related hospitalisations, and all-cause mortality.
Results: Interventions significantly improved LVEF compared with baseline (SMD: 0.53; 95% CI: 0.42-0.65; p < 0.00001) and control groups (SMD: 0.42; 95% CI: 0.31-0.53). Treatment reduced NYHA functional class (RR: 2.38; 95% CI: 1.48-3.84; p = 0.0004), all-cause mortality (RR: 0.62; 95% CI: 0.47-0.82; p = 0.0007), and HF-related hospitalizations (RR: 0.60; 95% CI: 0.42-0.85; p = 0.004). The certainty of evidence was rated as low across all outcomes owing to substantial heterogeneity and high risk of bias.
Discussion: These findings suggest a potential role for mitochondrial-targeted agents as adjunctive strategies in HF, although the evidence base requires further strengthening through high-quality, adequately powered trials before firm clinical recommendations can be made.
Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251075951, PROSPERO CRD420251075951.

Keywords:  HFpEF; HFrEF; coQ10; elamipretide; heart failure; mitochondrial energetics

DOI:  https://doi.org/10.3389/fcvm.2026.1824101
bioRxiv. 2026 Jul 08. pii: 2026.07.02.734998. [Epub ahead of print]

Dose and sex-specificity in Canagliflozin-mediated neuroprotection in aging mice.

Dulmalika Herath Manchanayake, Hashan Jayarathne, Sydney Scofield, Naduni Dasanthi Hitihami Mudiyanselage, Lindsey DeHaan, Omar Kadri, Nabeelah Rouf, Brett C Ginsburg, Richard A Miller, Marianna Sadagurski.

Canagliflozin (Cana), an SGLT2 inhibitor prescribed for type 2 diabetes, extends median lifespan by 14% in male but not female UM-HET3 mice at 180 ppm, with male-specific neuroprotective effects, despite females accumulating higher drug concentrations in blood and brain. Here, we tested whether reducing the dose to a subclinical level of 60 ppm could provide neuroprotective benefits in females by reducing drug accumulation. Starting treatment at 7 months of age, Cana at 60 ppm improved glucose tolerance in both sexes at 18 months and increased water and food intake, consistent with SGLT2 inhibition, but produced only a transient reduction in fat mass in males after one month on diet, with no sustained effect on body weight in either sex. At 60 ppm, Cana did not improve cognitive function at 18 months or reduce neuroinflammation in males, whereas females showed reduced hippocampal microgliosis and astrogliosis at 24 months. Pharmacokinetic analysis demonstrated that females accumulated 3-to 5-fold higher Cana concentrations than males across brain regions, blood, and liver. Together, these findings demonstrate that neither dose reduction nor greater drug accumulation drives neuroprotective benefit in females, indicating fundamental sex differences in the biological response to SGLT2 inhibition and suggesting that the sex-specific longevity effects of Cana are not simply a matter of dose.

DOI: https://doi.org/10.64898/2026.07.02.734998
Front Immunol. 2026 ;17 1881243

The mitochondrial logic of inflammaging: how energy imbalance drives fibroblast SASP and tissue-specific aging.

Yu Huan, Qiqi Wang, Rongkaixuan Fang, Yue Sun, Meiya Suo, Chenghong Cao, Shuya Zhang, Lan A, Wenzhou Xu.

  The conversion of metabolic disequilibrium into chronic inflammatory signaling represents a central and actively investigated question in ageing biology. Among stromal cells, fibroblasts are key effectors of tissue remodeling and inflammation, acquiring a senescence-associated secretory phenotype (SASP) that sustains age-related pathology. Here, we delineate a mechanistic framework in which disruption of energy homeostasis drives mitochondrial dysfunction, innate immune activation, and SASP secretion. Mitochondria act as metabolic sentinels that sense energetic stress through altered AMP/ATP and NAD+/NADH ratios, leading to the generation of mitochondrial danger signals-reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA). These signals converge on canonical immune pathways, including the cGAS-STING axis, NLRP3 inflammasome, and NF-κB signaling, thereby converting metabolic distress into persistent pro-inflammatory output. Using periodontal ligament fibroblasts as a disease-relevant model, we highlight how microbial biofilm exposure induces mitochondrial metabolic reprogramming that amplifies fibroblast SASP, promotes osteoclastogenesis, extracellular-matrix degradation, and alveolar bone resorption. At the transcriptional level, regulatory networks involving NF-κB, C/EBPβ, STATs, and the mTOR-AMPK hub integrate mitochondrial signals to sustain inflammatory senescence. We propose that restoring mitochondrial metabolic homeostasis serves as a highly promising strategy to break the self-perpetuating cycle in which energy imbalance triggers SASP activation, which in turn contributes to chronic inflammation. Researchers must first characterize the tissue-specific mitochondrial signatures of SASP. Subsequently, developing precise, lesion-targeted metabolic interventions will open new avenues for mitigating inflammaging and rejuvenating stromal function across ageing tissues.

Keywords:  cellular senescence; fibroblasts; inflammaging; innate immune signaling; metabolic reprogramming; mitochondrial dysfunction; senescence-associated secretory phenotype (SASP)

DOI:  https://doi.org/10.3389/fimmu.2026.1881243
Neurochem Int. 2026 Jul 17. pii: S0197-0186(26)00115-4. [Epub ahead of print] 106224

Is Urolithin A(UA) a Pharmacologically Credible Neuro-Nutraceutical? A Critical Review of Mechanisms, Brain Exposure, and Evidence Gaps in Alzheimer's and Parkinson's Disease.

Diya Girish Oswal, Meenal Rane.

  Urolithin A(UA) is a gut microbiota-derived metabolite of dietary ellagitannins and ellagic acid, generated by specific gut bacterial species and absent from food in free form. Preclinical evidence indicates that UA restores PINK1/Parkin-mediated mitophagy, attenuates NF-κB, NLRP3 inflammasome and cGAS-STING-driven neuroinflammation, and preserves synaptic and cognitive function across rodent and cell-culture models of Alzheimer's disease, Parkinson's disease, and age-related cognitive decline. However, circulating UA in humans exists predominantly as phase II glucuronide and sulfate conjugates rather than free aglycone, and human clinical evidence to date establishes UA's safety, favorable pharmacokinetics, mitochondrial target engagement, and benefits to muscle strength and physical function in middle-aged and older adults, with no completed trial yet evaluating cognitive or neurodegenerative disease-modifying outcomes. This review critically examines whether UA's neuroprotective mechanisms are pathway-specific and supported by convergent preclinical and human data, while explicitly separating mechanistic plausibility from demonstrated clinical efficacy.UA therefore represents a promising but still investigational neuro-nutraceutical candidate, with a mechanistic foundation strong enough to justify dedicated, CNS-endpoint-focused clinical trials as the next logical step toward establishing its neuroprotective potential in humans.

Keywords:  Blood-brain barrier; Mitophagy; Neurodegeneration; Neuroinflammation; PINK/Parkin; Urolithin A

DOI:  https://doi.org/10.1016/j.neuint.2026.106224
Biochem Biophys Res Commun. 2026 Jul 11. pii: S0006-291X(26)01036-3. [Epub ahead of print]830 154272

Ergothioneine attenuates age-related declines in circadian rhythmicity.

Kippei Wakita, Kazuto Watanabe, Takahiro J Nakamura.

  Aging is accompanied by the progressive deterioration of circadian clock function, characterized by reduced amplitude, increased period variability, and impaired metabolic coupling. Declining intracellular nicotinamide adenine dinucleotide (NAD+) levels and SIRT1 activity have been implicated as key mediators of age-associated circadian disruption. Ergothioneine (EGT), a diet-derived antioxidant with longevity-associated effects, has recently been reported to improve healthspan and modulate redox metabolism. However, its effects on the circadian clock remain unclear. Here, we examined whether EGT mitigates age-related decline in circadian rhythmicity using PER2::LUC mouse embryonic fibroblasts (MEFs). Chronic EGT treatment enhanced the amplitude of the PER2::LUC rhythm in a dose-dependent manner without markedly altering the baseline period length. Aging-associated NAD+ decline was modeled using FK866, a NAMPT inhibitor that depletes intracellular NAD+, which reduced rhythm amplitude, lengthened the period, and increased cycle-to-cycle variability. Notably, co-treatment with EGT significantly restored rhythm amplitude, attenuated FK866-induced period lengthening, and reduced period variability. Biochemical analyses revealed that EGT increased the NAD+/NADH ratio under basal conditions and significantly elevated both NAD+ levels and the NAD+/NADH ratio under FK866-induced NAD+ depletion. This effect was not attributable solely to cytoprotection. This study demonstrates that EGT enhances circadian rhythm robustness and counteracts NAD+-depletion-induced clock dysfunction. EGT may ameliorate age-related circadian decline by improving intracellular redox balance and NAD+ metabolism. Given that EGT crosses the blood-brain barrier, it may represent a novel nutritional strategy to preserve circadian function during aging.

Keywords:  Aging; Circadian rhythm; Clock gene; Ergothioneine; NAD(+)

DOI:  https://doi.org/10.1016/j.bbrc.2026.154272
EBioMedicine. 2026 Jul 17. pii: S2352-3964(26)00283-5. [Epub ahead of print]130 106399

Association between GDF-15 and sarcopenia progression in older adults: results from a population-based study.

Yuh-Shiou Gu, Alice Margherita Ornago, Caterina Gregorio, Chiara Ceolin, Anna Picca, Riccardo Calvani, Emanuele Marzetti, Birger C Forsberg, Davide Liborio Vetrano.

   BACKGROUND: Growth differentiation factor-15 (GDF-15), a stress-induced cytokine, has been implicated in pathways related to muscle degeneration, although findings regarding its association with sarcopenia remain heterogeneous. This study investigated the association between serum levels of GDF-15 and sarcopenia progression in community-dwelling older adults.
METHODS: 2347 individuals (mean age 72.3 years [SD 10.4]; 61.6% women), participating in the Swedish National Study on Aging and Care in Kungsholmen, were included in the study. Sarcopenia status (no, probable, and confirmed sarcopenia) were defined according to modified European Working Group on Sarcopenia in Older People 2 criteria. Twelve-year longitudinal sarcopenia trajectories were identified through latent class analysis. GDF-15 was measured in serum samples collected at baseline. Logistic regression was employed to assess the associations between GDF-15 and sarcopenia progression.
FINDINGS: Two trajectories of sarcopenia were identified: an early-progression pattern around the age of 70 and a later-progression pattern around the age of 80. Baseline sarcopenia prevalence differed between trajectories (p < 0.001), and GDF-15 levels were higher in the early trajectory (1.00 ng/mL vs. 0.86 ng/mL, p < 0.001). In adjusted multinomial logistic models, higher GDF-15 was associated with greater odds of probable (aOR = 1.6; 95% CI: 1.2-2.0) and confirmed sarcopenia (aOR = 1.9; 95% CI: 1.3-2.6). GDF-15 levels were also linked to increased odds of belonging to the early progression trajectory (aOR = 1.5; 95% CI: 1.2-1.9), with the association driven by the highest quintiles.
INTERPRETATION: GDF-15 reflects biological processes linked to muscle degeneration and may provide complementary information alongside established measures of sarcopenia in community-dwelling older adults.
FUNDING: The Swedish Research Council, the Swedish Ministry of Health and Social Affairs, and the County Councils and Municipalities.

Keywords:  Biomarker; Disease progression; Growth differentiation factor 15; Trajectory

DOI:  https://doi.org/10.1016/j.ebiom.2026.106399
Life Sci. 2026 Jul 13. pii: S0024-3205(26)00403-0. [Epub ahead of print]402 124594

Impaired mitochondrial flexibility hinders fat pad remodeling in obese mice after 24 h of fasting.

Mariele Lino Silva, Laura Dos Santos Fernandes, Joyce Elisa Heredia, Amanda Carla Clemente de Oliveira, Adma Maciel Babetto, Gustavo de Oliveira Zanetti, Dawit Albieiro Pinheiro Gonçalves, Mauro Martins Teixeira, Geneviève Marcelin, Marina Chaves de Oliveira, Adaliene Versiani Matos Ferreira.

  Obesity involves positive energy balance and mitochondrial dysfunction. Mitochondria play a vital role in reshaping tissues by oxidizing substrates; however, tissue-specific organellar plasticity during energy deprivation remains poorly characterized in obesity. We investigated the effects of 24-h fasting on mitochondrial dynamics in adipose tissue, liver, and muscle of lean and diet-induced obese (DIO) male C57BL/6 mice. Fasting reduced body weight by 13% and subcutaneous adipose tissue (SAT) by 40% in lean mice, but only 6.4% in DIO mice, which maintained SAT mass. Indirect calorimetry revealed an attenuated reduction in the respiratory exchange ratio (RER) in DIO mice during the fed-to-fasting transition. In lean mice, fasting triggered tissue-specific mitochondrial morphological adaptations, characterized by increased mitochondrial size in the SAT, liver, and muscle, alongside higher mitochondrial density in the liver. In contrast, DIO mice displayed blunted mitochondrial morphological plasticity. Interestingly, fasting increased endoplasmic reticulum (ER)-mitochondria proximity (MAMs) and modulated mitochondrial chaperone and protease expression in specific tissues of DIO mice. Furthermore, fasted DIO mice showed a downregulation of mtDNA-encoded genes and selected mitochondrial unfolded protein response (UPRmt) markers. In brown adipose tissue (BAT), mitochondrial architecture remained largely unaltered after fasting in both groups. These findings demonstrate that obesity impairs tissue-specific mitochondrial structural adaptations and blunts systemic metabolic flexibility during fasting. Conversely, acute fasting partially promotes ER-mitochondria ultrastructural proximity in obese mice in a tissue-specific manner, establishing a baseline for future functional interventions.

Keywords:  Fasting; Mitochondria; Mitochondria-ER interactions; Obesity; Transmission electron microscopy

DOI:  https://doi.org/10.1016/j.lfs.2026.124594
Cureus. 2026 Jun;18(6): e110935

Standardized Saffron Extract Formulation for Low Mood and Subclinical Depressive Symptoms: A Randomized, Double-Blind, Placebo-Controlled Trial.

Shishir Shah, Nishesh Shah, Jai Shah, Dyuthi S, Janani S, P Sudha Rani.

  Background and aim Low mood with subclinical to mild depressive symptoms represents an early stage of mood disorders with risk of progression to major depression. This study was conducted to evaluate the efficacy and safety of a standardized saffron extract formulation (UO SAF 02, 15 mg) in adults with self-reported low mood and subclinical to mild depressive symptoms. Methods In this randomized, double-blind, placebo-controlled trial, 56 adults aged 18-65 years with self-reported low mood and Beck Depression Inventory (BDI) scores of 10-20 were randomized (1:1) to receive UO SAF 02 or placebo for 56 days. The trial was registered with the Clinical Trials Registry of India (CTRI/2023/11/059603). The primary outcome was the change in total Profile of Mood States (POMS) scores. Secondary outcomes included measures of affective state (Positive and Negative Affect Schedule (PANAS)), depression, anxiety, and stress (Depression Anxiety Stress Scales (DASS-21)), sleep quality (Pittsburgh Sleep Quality Index (PSQI)), and serum cortisol levels. Results Compared with placebo, UO SAF 02 demonstrated significant and consistent improvements in mood-related outcomes, with statistically significant effects observed at Day 28 and maintained through Day 56. POMS scores decreased markedly in the UO SAF 02 group at Day 56 (-48.46 ± 5.39, p < 0.0005) versus the placebo group (-5.67 ± 3.44, p > 0.05). Significant improvements were also observed in affective states, with greater increases in positive affect and reductions in negative affect (p < 0.05), along with reductions in DASS-21 scores (p < 0.001) and improvements in sleep quality (PSQI; p < 0.05). Serum cortisol levels were significantly reduced at both Day 28 and Day 56 (p < 0.05). The intervention was well tolerated, with no serious adverse events reported. Conclusions UO SAF 02 significantly improved psychological and physiological mood-related outcomes in individuals with low mood and subclinical to mild depressive symptoms, supporting its potential as an effective and well-tolerated intervention for mood regulation.

Keywords:  crocus sativus; depressive symptoms; low mood; mood regulation; saffron; serum cortisol; sleep quality; subclinical depression

DOI:  https://doi.org/10.7759/cureus.110935