bims-mistre 2026-09-06 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–09–06
seventeen papers selected by
Ellen Siobhan Mitchell, MitoQ

Mitochondrial Respiration in Peripheral Blood Cells Links to Metabolic Flexibility and Physical Performance in Ageing.
Association of plasma growth differentiation factor-15 with the frailty phenotype - Evidence from the COGFRAIL study.
APOE4-AGE axis is linked to mtDNA release and cGAS-STING-mediated neuroinflammation in the aging brain.
A Systematic Review of the Vascular and Neuronal Role of L-Carnosine: Mechanistic and Pharmacological Perspectives.
Egg Peptides From American Shad Extend Lifespan and Healthspan in Caenorhabditis elegans via Lipid Metabolism Remodeling and Antioxidant Defense.
Microvascular endothelial function is blunted in postmenopausal females with frequent hot flushes.
The cognitive effects of creatine supplementation in older adults and preclinical models of dementia: A scoping review.
Identification of Cysl-2 as a Compensatory Factor in Vitamin B12-Mediated Protection in a Mitochondrial Aβ Toxicity Model.
Nicotinamide Adenine Dinucleotide and Its Anti-aging Effects in the Context of Longevity and Menopause.
Persistent mitochondrial and endothelial dysfunction in non-hospitalized patients with Long COVID.
Gut microbiota-mitochondria-barrier-multiorgan axis: a network-based hypothesis for systemic injury.
Preclinical evidence and multi-omics insights into the protective effects of epigallocatechin-3-gallate against high-fat diet-induced adverse health outcomes.
Effect of Hormone Replacement Therapy on Risk of Age-related Macular Degeneration Among an Aggregate Health Record Cohort.
Targeting hormone treatment for the brain in menopause.
Broccoli-licorice-passionflower blend improves mitochondrial function and exerts senotherapeutic effects.
Rosmarinic Acid Attenuates Isoniazid-Induced Neurotoxicity by Restoring Mitochondrial Dynamics and Suppressing Oxidative Stress, Ferroptosis, Neuroinflammation, and Apoptosis.
Age-related disruptions in ubiquitination and mitochondrial proteostasis are associated with neuronal compartment-specific mitochondrial changes.

J Cachexia Sarcopenia Muscle. 2026 Oct;17(5): e70361

Mitochondrial Respiration in Peripheral Blood Cells Links to Metabolic Flexibility and Physical Performance in Ageing.

Donna Li, Catrin Herpich, Christopher Bishop, Marie Aleithe, Antonia Peil, Nele Krüger, Jannes Felsner, Lea Göger, Maximilian Kleinert, Kristina Norman.

   BACKGROUND: Age-related declines in energy metabolism, muscle strength and physical performance have been linked to lower mitochondrial respiratory capacity. Peripheral blood mononuclear cell (PBMC) respiration offers a minimally invasive marker of systemic bioenergetics, yet its relationship to whole-body metabolic flexibility remains unclear. This study examined whether PBMC respiratory capacity is associated with substrate utilization during submaximal exercise, muscle strength and physical function in healthy older adults.
METHODS: PBMC mitochondrial respiratory capacity was quantified by high-resolution respirometry assessing ROUTINE, LEAK and MAX states. Postprandial substrate oxidation during steady-state treadmill walking at 60% of VO2max (oxygen uptake) was quantified by indirect calorimetry, and fat and carbohydrate oxidation rates were calculated using standard stoichiometric equations. Metabolic flexibility was defined as lower respiratory exchange ratio (RER) and higher relative fat oxidation at a fixed workload. Muscle strength was determined by handgrip dynamometry and one-repetition maximum leg extension. Physical function was evaluated by gait speed and five-repetition chair rise time. Associations were tested with linear and logistic regression adjusted for age, sex, skeletal muscle index, physical activity and high-sensitive C-reactive protein concentrations. Exploratory K-means clustering identified mitochondrial respiration phenotypes.
RESULTS: Fifty community-dwelling older adults (22 men, 28 women; age 70 ± 4 years) were examined. Higher ROUTINE respiration was correlated with RER (rho = -0.335, p = 0.020), fat utilization (rho = -0.334, p = 0.019), grip strength (rho = 0.302, p = 0.033) and gait speed (rho = 0.324, p = 0.022). Adjusted regression analyses confirmed the association of ROUTINE respiration with greater fat oxidation (β = 0.212, 95% CI 0.049; 0.375), lower RER (β = -0.160, 95% CI -0.300; -0.020) and higher gait speed (β = 0.153, 95% CI 0.028; 0.277). Similar associations were found for ATP-linked respiration. Cluster analysis identified high- and low-respiration phenotypes. Compared with the high-respiration group the low-respiration group showed lower CMJ height (OR: 0.204, 95% CI 0.055; 0.763) and quadriceps strength (OR: 0.373, 95% CI 0.155; 0.897).
CONCLUSIONS: In healthy older adults, higher PBMC ROUTINE respiration was associated with a more fat-dominant substrate utilization profile during submaximal exercise, greater muscle strength and faster gait speed. PBMC respiratory capacity may reflect systemic bioenergetic status relevant to exercise substrate utilization and physical performance in ageing.

Keywords:  ageing; metabolic flexibility; metabolism; mitochondrial respiratory capacity

DOI:  https://doi.org/10.1002/jcsm.70361
J Frailty Aging. 2026 Sep 04. pii: S2260-1341(26)00063-0. [Epub ahead of print]15(5): 100194

Association of plasma growth differentiation factor-15 with the frailty phenotype - Evidence from the COGFRAIL study.

Federico Bellelli, Juan Luis Sanchez Sanchez, Davide Angioni, Alexandre Lucas, Yves Rolland, Marco Proietti, Bruno Vellas, Philipe De Souto Barreto, Sandrine Sourdet.

   BACKGROUND: Growth differentiation factor-15 (GDF-15) has been consistently associated with physical frailty. However, it remains unclear whether GDF-15 further discriminates adverse outcomes among older adults who are already physically and cognitively impaired.
OBJECTIVES: To evaluate whether GDF-15 is associated with measures of physical frailty - incident weight loss, decline in muscle strength and gait speed, fatigue, and sedentary behaviours - over a 2-year follow-up.
DESIGN: Monocentric prospective study SETTING: Frailty and Memory Clinics, Gérontopôle Toulouse University-Hospital.
PARTICIPANTS: 206 pre-frail and frail older adults with cognitive impairment from the COGFRAIL study with available plasma GDF-15 concentrations (median age 82.0). Secondary analyses were performed in a subgroup with repeated GDF-15 measurements during follow-up (n = 129).
MEASUREMENTS: GDF-15 concentrations were analysed as a continuous variable and by tertiles. Exploratory analyses used two thresholds: 1500pg/mL (eligibility cut-off for GDF-15 inhibitor treatment in cancer-cachexia) and 2443pg/mL (upper tertile of the 6-month distribution).
RESULTS: Higher GDF-15 levels were associated with a steeper decline in handgrip strength over time (p = 0.047), with no significant associations for weight loss, gait speed, sedentary behaviour, or fatigue. By tertiles, participants in the highest tertile had greater handgrip strength decline compared to those in the lowest (p = 0.018). Participants in the intermediate group had a higher risk of worsening frailty (p = 0.013) and incident weight loss (SHR 2.51; 95% CI: 1.04-6.04; p = 0.040) compared with the lowest tertile. Individuals with persistently high or increasing GDF-15 concentrations (≥2443pg/mL) experienced greater decline in handgrip strength than those with persistently low levels (p < 0.001).
CONCLUSIONS: Higher plasma GDF-15 concentrations consistently predicted a steeper decline in muscle strength over time. Associations with incident weight loss and worsening frailty were also observed, although they appeared weaker at higher concentrations, possibly because of greater competing mortality in participants with very high GDF-15 levels. Further research should clarify the mechanisms linking GDF-15 to physical decline and weight loss, and whether targeting this pathway could help slow frailty progression.

Keywords:  Appetite; Frailty; Growth differentiation factor 15; Sarcopenia; Weight loss

DOI:  https://doi.org/10.1016/j.tjfa.2026.100194
Free Radic Biol Med. 2026 Aug 29. pii: S0891-5849(26)01056-7. [Epub ahead of print]256 312-322

APOE4-AGE axis is linked to mtDNA release and cGAS-STING-mediated neuroinflammation in the aging brain.

Firoz Akhter, Asma Akhter, Jasmine Zhou, Michelle Xi, Donghui Zhu.

  Advanced glycation end products (AGEs) accumulate with aging and have been implicated in neurodegeneration, yet their relationship with the APOE4 genotype and downstream inflammatory signaling remains poorly understood. Here, we show that APOE4 is associated with greater age-dependent AGE accumulation and APOE glycation in the aging brain compared with APOE3 in animal models. These changes are accompanied by mitochondrial dysfunction and increased release of mitochondrial DNA (mtDNA) into the cytosol, providing a potential trigger for innate immune activation. Consistent with enhanced innate immune signaling, APOE4 brains exhibit increased cGAS expression and phosphorylation of STING, TBK1, and IRF3, together with elevated type I interferon and pro-inflammatory responses. This activation is particularly prominent in microglia, as demonstrated by increased cGAS-DNA interactions and greater colocalization of cGAS signaling with Iba1-positive cells. APOE4 mice further display increased levels of cGAMP and IFN-β, as well as enhanced expression of pro-inflammatory cytokines and interferon-stimulated genes. Mechanistically, exposure of primary microglia to AGEs induces cytosolic mtDNA release and activates cGAS-STING signaling, whereas pharmacological inhibition of the receptor for advanced glycation end products (RAGE) attenuates these responses. Together, these findings identify an association between the APOE4-AGE axis, mitochondrial dysfunction, mtDNA release, and enhanced cGAS-STING-related inflammatory signaling in the aging brain, while the in vitro studies support a functional contribution of AGE-RAGE signaling to these responses in primary microglia.

Keywords:  APOE4; Advanced glycation end products (AGEs); Microglia; Mitochondrial DNA; Neuroinflammation; cGAS-STING signaling

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.08.054
Curr Neuropharmacol. 2026 Aug 25.

A Systematic Review of the Vascular and Neuronal Role of L-Carnosine: Mechanistic and Pharmacological Perspectives.

Nidhi Tiwari, Vivek Kumar, Bhuwan Chandra Joshi, Abdulaziz S Saeedan, Summya Rashid, Mohd Nazam Ansari.

   INTRODUCTION: L-carnosine is a powerful natural antioxidant found in the brain, muscles, and digestive systems of all vertebrates, including humans, that helps fight Reactive Oxygen Species (ROS) and other harmful byproducts of oxidative stress. L-carnosine has antioxidant properties as well as the ability to bind with metal ions and prevent glycation, a process that can damage cells. This review article highlights the protective effects of L-carnosine against a variety of pathological conditions, such as Alzheimer's Disease (AD), Parkinson's Disease (PD), ischemia‒reperfusion injury, Huntington's disease, stroke, depression, traumatic brain injury, cancer, diabetes, ageing, etc. Among these conditions, mitochondrial dysfunction and increased oxidative stress are common. Moreover, methylglyoxal (MG), another metabolic product, and Advanced Glycation End products (AGEs) damage cells through interactions with proteins. Through receptor-mediated endocytosis, macrophages absorb them and release proinflammatory chemicals that induce severe inflammation and lead to cell death.
METHODS: Search engines, including PubMed, ScienceDirect, ProQuest, Scopus, ResearchGate, MDPI, journals, websites, and databases such as Google Scholar, were thoroughly searched and reviewed. The search strategy for articles published between 2000 and 2025 used various combinations of key Medical Subject Headings (MeSH) terms and phrases, including L-carnosine, alanine, histidine, Randomized Controlled Trial (RCT), aging, cancer, cardiovascular disease, diabetes, and neurodegenerative disorders, and various non-MeSH terms.
RESULTS: L-carnosine exhibits protective effects on models of neurological, ischemic, metabolic, and malignant diseases because of its antioxidant, anti-inflammatory, and neuroprotective properties. In Alzheimer's disease, carnosine specifically increases the production of heat shock proteins (Hsps). In Parkinson's disease, it increases dopamine levels and stops alpha-synuclein protein accumulation. In ischemia‒reperfusion injury, L-carnosine inhibits the release of inflammatory mediators such as cytokines and TNF-alpha. In cancer, it inhibits the Mitogen-Activated Protein Kinase (MAPK)/ Extracellular Signal-Related Kinase (ERK) signaling pathway. It mitigates aging-related damage to proteins. Additionally, L-carnosine inhibits the formation of MG and AGEs, suggesting its potential therapeutic efficacy in a range of diseases.
DISCUSSION: L-carnosine shows multitarget therapeutic potential through antioxidant, anti-inflammatory, and antiglycation actions, as well as mitochondrial protection. It influences key pathways involved in neurodegeneration, including protein aggregation and oxidative stress. Evidence from preclinical and early clinical studies suggests benefits in neurological and metabolic disorders. Despite promising outcomes, challenges such as rapid degradation and limited bioavailability affect clinical translation. Further studies are needed to define the optimal dosing and therapeutic use.
CONCLUSION: L-carnosine acts as a cytoprotective molecule in multiple ways, including mitigating oxidative stress, protein glycation, mitochondrial dysfunction, and inflammation, thereby modulating pathways characteristic of chronic illnesses. By altering these interconnected pathways, L-carnosine has the potential for several therapeutic applications as an adjuvant for a range of neurological, metabolic, ischemic, cancer, and aging-related illnesses.

Keywords:  L-Carnosine; advanced glycation end products; central nervous system; mitochondrial dysfunction; neurodegeneration; oxidative stress

DOI:  https://doi.org/10.2174/011570159X462604260803095102
Chem Biodivers. 2026 Sep;23(9): e71648

Egg Peptides From American Shad Extend Lifespan and Healthspan in Caenorhabditis elegans via Lipid Metabolism Remodeling and Antioxidant Defense.

Jia Du, Qinghua Liu, Zhongxiao Wan, Naomi Sudo, Yanyang Xu.

  Given the increasing focus on natural interventions for healthy aging, this research evaluates the longevity-promoting potential of egg-derived peptides (EPs) extracted from American shad (Alosa sapidissima). Using Caenorhabditis elegans as the experimental model, researchers found that 0.15 mg/mL EP supplementation extended lifespan by a remarkable 33.33%. EP also significantly enhanced healthspan, improving physiological metrics such as head thrashing, body bending, and pharyngeal pumping by 24.37%, 22.33%, and 28.81%, respectively. Furthermore, EP reduced aging biomarkers-including lipofuscin and reactive oxygen species (ROS)-by up to 40.34%, while boosting overall antioxidant capacity (SOD increased by 53%, MDA decreased by 30.76%). Transcriptomic analysis identified 2196 differentially expressed genes (DEGs) out of 23 057 total identified genes, providing deep insights into the mechanisms underlying EP-mediated longevity. Crucially, EP upregulated genes responsible for unsaturated fatty acid biosynthesis (fat-7 and elo-4) to optimize cell membrane fluidity. Conversely, it downregulated genes linked to fatty acid β-oxidation (acs-2, acox-1.5, ech-9, hacd-1) and endogenous stress responses (sod-3, hsp-16.1, hsf-1). Validated via qRT-PCR, these shifts indicate that EP extends lifespan by fundamentally remodeling lipid metabolism and maintaining redox homeostasis. Ultimately, these findings highlight EP as a highly promising functional food ingredient for promoting healthy aging.

Keywords:  Caenorhabditis elegans; antiaging; egg peptides; oxidative stress; transcriptomics

DOI:  https://doi.org/10.1002/cbdv.71648
Exp Physiol. 2026 Sep 01.

Microvascular endothelial function is blunted in postmenopausal females with frequent hot flushes.

William Stokes, Chowdhury Tasnova Tahsin, Miguel F Anselmo, Stephany Nathe, Emma J Lee, Soliana Teshome, Marnie L Vanden Noven, Anne Blaes, Benjamin W Langworthy, Manda L Keller-Ross.

  Hot flushes of menopause are associated with elevated blood pressure (BP) and diminished macrovascular endothelial function, an initiating factor in the onset of atherosclerosis. Whether microvascular endothelial function is impaired in females with hot flushes, however, remains unknown. We hypothesised that postmenopausal females with hot flushes would have reduced microvascular endothelial function and elevated BP in comparison to age-matched females without hot flushes. Participants were healthy postmenopausal females, aged 45-70 years; participants experiencing at least three hot flushes per day were placed in the hot flush (HF) group (n = 16), whereas participants with no history of hot flushes were placed in the non-HF group (n = 18). Heart rate (ECG) and BP (finger plethysmography) were measured during a 10 min rest period, and endothelial function was measured with pulse amplitude tonometry (EndoPAT 2000), quantified by the reactive hyperaemia index (RHI) and the natural logarithm of the RHI (LnRHI). Groups were similar in age, age at menopause and body mass index, in addition to systolic BP, diastolic BP and heart rate between groups (P > 0.05). The RHI was lower in the HF group (1.87 ± 0.47 a.u.) compared with the non-HF group (2.31 ± 0.67 a.u., P = 0.047), and the difference between LnRHI in the HF group (0.63 ± 0.21 a.u.) and the non-HF group was nearly significant (0.80 ± 0.27 a.u., P = 0.052). New findings from this study demonstrate a lower microvascular endothelial function in females with hot flushes in comparison to females without hot flushes, although BP and heart rate were not different between the groups. The reduced microvascular endothelial function demonstrated in females with hot flushes is likely to contribute to greater cardiovascular disease development.

Keywords:  cardiovascular disease; menopause; vasomotor symptoms

DOI:  https://doi.org/10.1113/EP093733
Ageing Res Rev. 2026 Aug 29. pii: S1568-1637(26)00309-0. [Epub ahead of print]122 103317

The cognitive effects of creatine supplementation in older adults and preclinical models of dementia: A scoping review.

Tobias Whitford, Christian Donlon, Aidan Pech, Chase Goldberg, Harris Whiteson, Mill Etienne.

   BACKGROUND & OBJECTIVES: Dementia represents a growing global health crisis, yet disease-modifying therapies remain limited. Impaired brain energy metabolism, neuroinflammation, and synaptic dysfunction are some shared pathological features across dementia subtypes that may be amenable to metabolic intervention. Creatine supplementation, through its role in the phosphocreatine/ATP buffering system and proposed neuroprotective properties, has attracted growing scientific and public interest as a candidate intervention for dementia. This scoping review maps the existing evidence on creatine supplementation and dementia-related cognitive outcomes, with attention to intervention characteristics including dose, duration, formulation, route of administration as well as the characteristics of preclinical models.
METHODS: Following the Joanna Briggs Institute (JBI) methodology and Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines, a systematic search of PubMed, Embase, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL) was conducted. No date restrictions were applied to the search; eligibility was limited to English-language reports. Studies were eligible if they evaluated creatine supplementation in older adults or preclinical animal models with dementia and reported at least one cognitive outcome.
RESULTS: From 8317 records identified and screened, six studies reported across seven publications, met eligibility criteria comprising one in vitro study, four in vivo animal model studies, and one human pilot trial resulting in two publications. No relevant randomized controlled trials (RCTs) were identified in the search. Evidence was heterogeneous across study design, population, and intervention characteristics. Preclinical studies demonstrated predominantly neuroprotective effects through bioenergetic support and neuroinflammatory modulation, though one rodent study reported worsening spatial memory. A single human pilot trial (n = 20) found that high-dose supplementation (20 g/day for 8 weeks) increased brain total creatine by 11% and was associated with improved fluid cognition. Sex-specific effects were identified in one rodent study, with female animals demonstrating cognitive benefit and males showing a trend toward harm. This was paralleled by sex-divergent bioenergetic responses in the human trial.
CONCLUSION: Current evidence for creatine supplementation in dementia is limited, heterogeneous, and predominantly preclinical. While not supporting a causal inference, preliminary human data does suggest biological plausibility and feasibility, supporting the need for adequately powered, sex-stratified randomized controlled trials in adults with dementia. While preclinical data support a mechanistic rationale for its use, this review identifies critical gaps including the absence of any controlled clinical trials, limited understanding of optimal dosing for brain penetrance, and the need to prospectively examine sex as a biological moderator of treatment response.

Keywords:  Bioenergetics; Cognition; Creatine; Dementia; Neuroprotection

DOI:  https://doi.org/10.1016/j.arr.2026.103317
J Agric Food Chem. 2026 Aug 26. 74(33): 26389-26400

Identification of Cysl-2 as a Compensatory Factor in Vitamin B12-Mediated Protection in a Mitochondrial Aβ Toxicity Model.

Qihui Huang, Junjie Fu, Lizhu Zhang, Jingyue Yao, Hui Cao, Lingjun Zheng, Chao Zhao, Jianbo Xiao.

  Alzheimer's disease (AD) is a highly sophisticated disease associated with mitochondrial deterioration, which potentiates proteotoxic stress and accelerates neuronal decline. Vitamin B12 (B12), an essential cofactor in one-carbon metabolism and cellular homeostasis, plays a pivotal role in modulating neurodegenerative pathology. Here, we established a mitochondrial-associated AD model by using Caenorhabditis elegans (C. elegans) expressing Aβ combining with the mtDNA deletion uaDf5, and evaluated the effect of B12 as a metabolic modulator of neurodegenerative stress. We observed that mitochondrial dysfunction markedly exacerbated Aβ phenotypes, while B12 mitigated paralysis and cellular deficits. Integrated transcriptomics and proteomics revealed a compensatory mechanism activated by B12 under mitochondrial stress, predominantly engaging one-carbon and transsulfuration pathways. Functional analyses uncovered that metr-1 and cysl-2 are required for B12-mediated protection, and multiomics corroborated this rescue axis. This study indicates that cysl-2 is an essential mediator and reveals a B12-driven adaptive response, which provides mechanistic insight into nutrition-based neuroprotection in AD.

Keywords:  Alzheimer’s disease; C. elegans; mitochondrial dysfunction; vitamin B12

DOI:  https://doi.org/10.1021/acs.jafc.6c07935
Mini Rev Med Chem. 2026 Aug 18.

Nicotinamide Adenine Dinucleotide and Its Anti-aging Effects in the Context of Longevity and Menopause.

Elifsena Canan Alp Arici, Esra Küpeli Akkol, Eduardo Sobarzo-Sánchez, Zeliha Selamoglu.

  Menopause is a complex biological condition associated with progressive estrogen depletion and increased susceptibility to several age-associated disorders. During this process, several biological mechanisms, such as mitochondrial dysfunction, oxidative stress, chronic inflammation, genomic instability, and immunosenescence, contribute to the progression of biological aging and metabolic imbalance. In this sense, nicotinamide adenine dinucleotide (NAD⁺) has progressively attracted attention because of its important role in mitochondrial homeostasis, DNA repair pathways, cellular energetics, and inflammatory regulation. This narrative review discusses the mechanistic relationship between NAD⁺ metabolism, aging, and menopause by integrating experimental and clinical evidence currently available in the literature. The review was developed using PubMed, Scopus, and Web of Science databases, considering studies associated with menopause, aging, NAD⁺ metabolism, nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), mitochondrial dysfunction, and inflammatory signaling pathways. According to the evidence currently available, depletion of intracellular NAD⁺ levels during aging may contribute to mitochondrial dysfunction, impaired metabolic regulation, chronic inflammatory signaling, and neurodegenerative alterations. Although NAD⁺ precursors such as NMN and NR have shown promising biological effects in experimental studies, some limitations are still evident when these findings are translated to humans, including pharmacokinetic instability, tissue-specific bioavailability, and variability in clinical responses. Moreover, chronic inflammation and CD38 overexpression appear strongly associated with progressive intracellular NAD⁺ depletion during aging and menopause. Thus, modulation of NAD⁺ metabolism may represent a promising strategy in longevity medicine and menopausal health. However, despite the important mechanistic advances achieved in recent years, long-term clinical evidence is still insufficient to support a definitive therapeutic conclusion. Therefore, more experimental and clinical studies are still required to establish the real therapeutic relevance and safety of NAD⁺-targeted interventions in menopausal women.

Keywords:  Aging; Menopause; NAD⁺; NMN; anti-aging; longevity; mitochondrial function; women’s health

DOI:  https://doi.org/10.2174/0113895575469704260805105227
Front Med (Lausanne). 2026 ;13 1921822

Persistent mitochondrial and endothelial dysfunction in non-hospitalized patients with Long COVID.

Rie Ono, Shin Takayama, Michiaki Abe, Ryutaro Arita, Koh Onodera, Kota Ishizawa, Takeshi Kanno, Natsumi Saito, Akiko Kikuchi, Takaaki Abe, Tadashi Ishii.

  Long COVID, a major post-acute infection syndrome (PAIS), characterized by prolonged or new-onset symptoms following acute COVID-19, critically affects patients' quality of life. Establishing easily measurable and objective biomarkers that reflect disease severity is essential for clinical management. This retrospective cohort study evaluated serum levels of growth differentiation factor 15 (GDF-15), a mitochondrial stress marker, and vascular cell adhesion molecule-1 (VCAM-1), a vascular endothelial stress marker, in 32 patients with Long COVID who presented with persistent systemic or neurological symptoms and had not required acute-phase hospitalization. Serum GDF-15, VCAM-1, and inflammatory cytokine levels were measured at the initial visit and at 3 and 6 months. Differences between patients who recovered at 6 months and those who did not (non-improved group) were analyzed using linear mixed-effects models (LMMs). Most inflammatory cytokines remained near their lower detection limits and were excluded from the longitudinal analysis. The LMMs revealed sustained elevation of both GDF-15 (p = 0.02) and VCAM-1 (p = 0.03) levels in the non-improved group. These findings suggest that longitudinal tracking of these two markers may offer clinically relevant insights into disease activity and treatment-resistant pathophysiology in mild acute-phase Long COVID.

Keywords:  Long COVID; biomarkers; endothelial dysfunction; growth differentiation factor 15 (GDF-15); mitochondrial dysfunction; vascular cell adhesion molecule-1 (VCAM-1)

DOI:  https://doi.org/10.3389/fmed.2026.1921822
Front Immunol. 2026 ;17 1885379

Gut microbiota-mitochondria-barrier-multiorgan axis: a network-based hypothesis for systemic injury.

Yachao Li, Huaijue Qiu, Xiang Gao, Yanling Zhang, Qin Xia.

  Intestinal barrier failure is considered a driver of multiple organ dysfunction syndrome (MODS) in critical illness; however, the precise molecular mechanisms linking altered gut microbes to systemic injury remain unclear. Here we propose a testable hypothesis: mitochondrial dysfunction within intestinal epithelial cells (IECs) acts as a mechanistic hub connecting microbial dysbiosis to barrier breakdown and eventual multiorgan damage. This system is not a unidirectional chain but a highly network-based process with bidirectional feedback loops, context-dependent interactions, and hypothetical cross-talk that require experimental validation. We review evidence that microbial metabolites-short-chain fatty acids, hydrogen sulfide, secondary bile acids-directly modulate mitochondrial respiration, membrane potential, and reactive oxygen species (ROS) production in the gut lining. Once mitochondrial quality control falters, the cell suffers adenosine triphosphate (ATP) depletion, excessive ROS, calcium-driven calpain activation, and leakage of mitochondrial damage-associated molecular patterns (mtDAMPs) like mitochondrial DNA (mtDNA) into the cytoplasm. These mtDAMPs ignite the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and the NLR family pyrin domain containing 3 (NLRP3) inflammasome, disrupting tight junctions and converting the intestinal barrier into an active inflammatory broadcaster. Critically, the inflammatory response is amplified by immune intermediary layers, including neutrophil extracellular trap (NET) formation, monocyte/macrophage metabolic reprogramming, endothelial activation, and complement activation, which bridge local barrier disruption to systemic organ injury. When mtDAMPs reach the circulation, they trigger sterile inflammation in distant organs through shared innate immune sensors (Toll-like receptor 9 [TLR9] and NLRP3) in liver, lung, and brain. A word of caution: circulating mtDNA originates from multiple tissues (e.g., immune cells, skeletal muscle, liver) and therefore represents a systemic DAMP, not a gut-specific signal; its interpretation requires contextual information on tissue origin and temporal dynamics. Human evidence still lacks clear answers on temporal order, directionality, epigenetic mediation, and quantitative thresholds. We discuss how circulating metabolites and mtDNA could serve as candidate monitoring biomarkers to turn this conceptual network into a testable, quantitative model. Finally, we outline a multi-dimensional research framework (metabolite replenishment, mitophagy enhancement, epigenetic tuning) while stressing that any clinical application must await prospective validation. For now, the "microbiota-mitochondria-barrier-multiorgan" axis should be seen as a well-grounded hypothesis, not an established fact.

Keywords:  gut microbiota; intestinal barrier; mitochondrial damps; mitochondrial dysfunction; multiple organ dysfunction syndrome; systemic inflammation

DOI:  https://doi.org/10.3389/fimmu.2026.1885379
Phytomedicine. 2026 Aug 23. pii: S0944-7113(26)00981-5. [Epub ahead of print]161 158750

Preclinical evidence and multi-omics insights into the protective effects of epigallocatechin-3-gallate against high-fat diet-induced adverse health outcomes.

Mengsong Liu, Jia Jiang, Zexin Wang, Xiao Ma, Jinhao Zeng, Jianyuan Tang.

   BACKGROUND: High-fat diet (HFD) consumption is associated with a range of adverse health outcomes, including dyslipidemia, non-alcoholic fatty liver disease (NAFLD), and type 2 diabetes mellitus (T2DM). Despite lifestyle interventions, patient adherence remains poor. Epigallocatechin-3-gallate (EGCG), a green tea catechin, shows therapeutic potential against HFD-induced adverse health outcomes. However, the systematic evaluation of its efficacy remains lacking.
PURPOSE: By integrating meta-analysis, machine learning, in vivo evaluation, proteomics, and public single-cell RNA sequencing (scRNA-seq), this study aimed to systematically evaluate the therapeutic potential of EGCG against HFD-induced adverse health outcomes.
METHODS: We meta-analyzed 79 rodent studies and developed machine learning models to explore outcome-specific dose and intervention-duration patterns for different metabolic outcomes. In the in vivo experiments, C57BL/6 mice were fed HFD and administered EGCG by gavage for 8 weeks. Additionally, liver and small intestine proteomics, reverse transcription quantitative polymerase chain reaction (RT-qPCR), immunofluorescence (IF) assessment, and UCell enrichment analysis of public NAFLD scRNA-seq data were performed.
RESULTS: The meta-analysis of 79 preclinical studies showed that EGCG attenuated weight gain, dyslipidemia, hepatic lipid accumulation and injury, hyperglycemia, inflammation, and oxidative stress. Machine-learning analyses revealed outcome-specific differences in predicted dose and intervention-duration patterns across blood lipids, hepatic lipids, and blood glucose. Proteomics analysis indicated that glycerophospholipid metabolism was a common pathway for EGCG in both the liver and the small intestine. RT-qPCR and IF were used to assess the expression of molecules related to glycerophospholipid metabolism. Public scRNA-seq analysis provided a potential hepatic cell-subtype context for the proteomics-derived lipid-metabolism signature.
CONCLUSION: This study has established a systematic preclinical evidence framework for evaluating the therapeutic potential of EGCG in addressing HFD-induced adverse health outcomes. Glycerophospholipid metabolism may be the common pathway through which EGCG protects the liver and small intestine.

Keywords:  Epigallocatechin-3-gallate; High-fat diet; Machine learning; Meta-analysis; Proteomics; Single-cell RNA sequencing

DOI:  https://doi.org/10.1016/j.phymed.2026.158750
Ophthalmic Surg Lasers Imaging Retina. 2026 Aug 31. 1-9

Effect of Hormone Replacement Therapy on Risk of Age-related Macular Degeneration Among an Aggregate Health Record Cohort.

Charles W Guo, Alison H Zhao, David Kaelber, Rishi P Singh, Katherine E Talcott.

BACKGROUND AND OBJECTIVE: Estrogen in hormone replacement therapy (HRT) exerts anti-inflammatory effects believed to oppose age-related macular degeneration (AMD) pathogenesis, but whether HRT can be protective against AMD is contested. The aim of the study was to evaluate the association between HRT use and the risk of development and progression of AMD in postmenopausal women.
PATIENTS AND METHODS: This was a retrospective cohort study utilizing ICD-10 codes for HRT usage and rates of AMD development and progression.
RESULTS: There was a decreased risk of developing AMD in patients more than 60 years of age at 5 years (RR 0.72, 95% CI: 0.63-0.82) and 8 years (0.68, 0.60-0.76) after HRT initiation. Patients more than 75 years of age also demonstrated a reduced risk of developing AMD after 5 years (0.70, 0.60-0.82) and 8 years (0.64, 0.56-0.74) of HRT use. Patients more than 75 years of age had a reduced risk of progression to exudative AMD at 8 years (0.66, 0.49-0.89) after HRT initiation.
CONCLUSION: HRT may be associated with a decreased risk of developing AMD, with continued effects at more chronic timepoints after HRT initiation.

DOI: https://doi.org/10.3928/23258160-20260813-03
Sci Rep. 2026 09 01. pii: 25901. [Epub ahead of print]16(1):

Targeting hormone treatment for the brain in menopause.

Noriko Itoh, Yuichiro Itoh, Rajita Patil, Christi Till, Marissa Smith, Jaclyn Schwartz, Brittany Davis, Erica Oberman, Brianne D Romeroso, Rhonda R Voskuhl.

  Estrogens are neuroprotective, and menopause may contribute to neurodegeneration. Estriol preferentially binds estrogen receptor beta (ERβ) in brain to induce neuroprotection. Previously, oral estriol improved cognitive processing speed and reduced cerebral cortex atrophy at treatment month twelve in women with multiple sclerosis (MS). Here, treatment with a blisterpack designed for healthy menopausal women which contains estriol and progesterone (Pearlpak) was assessed for its effect on cognitive domain-specific symptoms in a case series of twenty menopausal women (mean age 53.5 years). At treatment month twelve, there were significant improvements in self-reported brain fog, concentration, working memory, processing speed, verbal memory, and problem solving. A preclinical model explored mechanisms. Midlife female mice (age 12-13 months), previously ovariectomized either at 2 months or at 11 months of age, exhibited cognitive deficits on Morris Water Maze, with glial activation and synaptic loss on dorsal hippocampal pathology. Astrocytes had increased levels of Enolase 1 (ENO1), a key protein in glucose utilization. Increased ENO1 correlated with worse cognitive performance. Deletion of ERβ in astrocytes in gonadally intact midlife females recapitulated deleterious effects of ovariectomy. Conversely, treatment of midlife female mice with estriol from age 11 months to age 12 months reduced ENO1 expression in hippocampal astrocytes, reduced glial activation and synaptic loss, and improved cognitive performance. This preliminary study suggests that Pearlpak treatment for cognitive symptoms of menopause warrants further investigation given the safe use of these hormones in Europe and Asia for decades to reduce other menopausal symptoms.

Keywords:  Astrocyte; Cognition; Estriol; Estrogen receptor β; Menopause; Menopause Hormone Therapy (MRT)

DOI:  https://doi.org/10.1038/s41598-026-65603-4
Food Sci Biotechnol. 2026 Sep;35(11): 3409-3421

Broccoli-licorice-passionflower blend improves mitochondrial function and exerts senotherapeutic effects.

So-Hyun Park, Hee Soo Kim, Pyeong Geun Choi, Eunyoung Lee, Do Yun Cho, Sun Ho Kim, Hui Yun Kim, Ahjin Kim, Jiyun Ahn, Chang Hwa Jung.

  Aging is driven by multiple interconnected mechanisms, necessitating interventions that target multiple hallmarks of aging. Using a data-driven prioritization strategy, we screened 16 extract combinations generated from four candidate extracts (broccoli, licorice, passionflower, and lemon balm) and identified an optimized formulation, Blend 2, composed of broccoli, licorice, and passionflower extracts. Blend 2 restored mitochondrial respiration, ATP production, and citrate synthase activity under DNA damage-induced mitochondrial dysfunction through activation of the SIRT1-AMPK-PGC-1α pathway and enhanced mitophagy. It also exhibited dual senotherapeutic activity by suppressing the senescence-associated secretory phenotype via NF-κB inhibition and selectively eliminating senescent cells through the Bax/caspase pathway. These findings demonstrate that data-driven formulation strategies can identify multifunctional natural product combinations and establish Blend 2 as a promising candidate for targeting multiple hallmarks of aging.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s10068-026-02265-y.

Keywords:  Cellular senescence; Mitochondrial biogenesis; Mitophagy; Natural product blend; Senotherapeutics

DOI:  https://doi.org/10.1007/s10068-026-02265-y
Tissue Cell. 2026 Aug 27. pii: S0040-8166(26)00573-2. [Epub ahead of print]104(Pt 2): 103878

Rosmarinic Acid Attenuates Isoniazid-Induced Neurotoxicity by Restoring Mitochondrial Dynamics and Suppressing Oxidative Stress, Ferroptosis, Neuroinflammation, and Apoptosis.

Merve Bolat, Tuba Karaarslan, Samet Teki̇n, Esra Derelİ, Aslıhan Atasever, Burak Batuhan Laçi̇n, Esra Aktaş Şenocak, Furkan Aykurt, Emin Şengül, Fikret Çelebi̇, İsmail Bolat.

  Despite the continued global burden of tuberculosis and the essential role of isoniazid (INH) in first-line antituberculosis therapy, INH-induced neurotoxicity remains a major clinical challenge that compromises treatment adherence, and effective, well-characterized neuroprotective strategies are still lacking. This study investigated the neuroprotective effects of rosmarinic acid (RA) against INH-induced neurotoxicity, evaluating oxidative stress, inflammation, iron metabolism, energy homeostasis, mitochondrial dynamics, ferroptosis, and apoptosis using biochemical, molecular, and histopathological approaches. INH markedly increased malondialdehyde while reducing superoxide dismutase and glutathione, and increased TNF-α, IL-1β, and IL-6 while decreasing IL-10. INH also disturbed iron homeostasis (increased Fe²⁺), impaired energy metabolism (reduced ATP), and disrupted mitochondrial dynamics (increased Drp-1; decreased Mfn-2 and PGC-1α). NF-κB activation was accompanied by increased ACSL4 and decreased GPX4 and FTH1, reflecting ferroptosis, alongside increased Bax, Caspase-3, and Cytochrome c and reduced Bcl-2, indicating mitochondrial apoptosis. RA treatment suppressed oxidative stress, enhanced antioxidant defense, attenuated inflammation, restored iron and energy homeostasis, improved mitochondrial dynamics, and inhibited NF-κB activation, ferroptosis, and apoptosis. These findings demonstrate that RA exerts potent neuroprotective effects against INH-induced brain injury by simultaneously targeting oxidative stress, mitochondrial dysfunction, iron dyshomeostasis, neuroinflammation, ferroptosis, and apoptosis. To our knowledge, this is among the first studies to comprehensively address these interconnected pathways, including ferroptosis and iron dyshomeostasis, in INH-induced neurotoxicity. RA may thus represent a promising therapeutic candidate for preventing INH-induced neurotoxicity.

Keywords:  Ferroptosis; Iron homeostasis; Isoniazid; Mitochondrial dynamics; Neurotoxicity; Rosmarinic acid

DOI:  https://doi.org/10.1016/j.tice.2026.103878
Exp Gerontol. 2026 Sep 02. pii: S0531-5565(26)00282-2. [Epub ahead of print]224 113303

Age-related disruptions in ubiquitination and mitochondrial proteostasis are associated with neuronal compartment-specific mitochondrial changes.

Margaret-Jade Searles, Debanjali Dasgupta, Trace A Christensen, Gary C Sieck, Matthew J Fogarty.

  Declining aerodigestive neuromotor function is a major aspect of human aging, with impaired airway defense and swallow manoeuvres implicated in pneumonia and dysphagia. Hypoglossal motor neurons (MNs) innervate tongue muscles, essential for these behaviours. Their degeneration contributes to age-related aerodigestive dysfunctions. In neurodegenerative diseases, the ubiquitin-proteasome system (UPS) is altered, disturbing mitochondrial proteostasis. We have previously shown reduced mitochondrial abundance, dysfunction and mitochondrial fragmentation in aging hypoglossal MN somas and dendrites. However, the relationship between the UPS (pUBS65 and ubiquitinated proteins), mitochondrial fragmentation (pDRP1S616) and fusion promoting proteins (MFN2) in MN aging is unexplored. In other neurons, aging changes mitochondria within axons in an opposite way to somas and dendrites. We used Western blotting to show impairment in mitophagy-related pUBS65, increased fragmentation-promoting pDRP1S616 and unchanged MFN2. Serial Block-Face Scanning Electron Microscopy showed increased mitochondrial volume density and larger, more simplistic mitochondria in old, myelinated hypoglossal axons, while somas and dendrites showed reduced mitochondrial volume density and increased fragmentation. Our results suggest that a more nuanced compartment-specific evaluation of mitochondrial structure and function is required to fully elucidate the pathophysiology underlying age-related neuromotor dysfunction.

Keywords:  Aging; Axon; Brainstem; Dendrite; Hypoglossal; Mitochondria; Motor neuron; Proteostasis

DOI:  https://doi.org/10.1016/j.exger.2026.113303