bims-mistre 2026-09-27 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–09–27
25 papers selected by
Ellen Siobhan Mitchell, MitoQ

Mitochondrial Fusion and Fission in Age-Related Cardio-Cerebral Diseases: Mechanisms and Interventions.
SIRT1 in Senescence: Mitochondria and Immune Crosstalk.
Blood proteomics of menopause map to brain aging and dementia risk.
Association of plasma growth differentiation factor 15 with wake after sleep onset in mild cognitive impairment.
Ketone ester supplementation in aged mice produces sex-specific cognitive and metabolic effects.
Oxidative Stress in Vascular Aging: Therapeutic Potential of the Antioxidant Paradox. A State-of-the-Art Review.
Evaluating the Therapeutic Potential of Antioxidants in Polyendocrine Metabolic Ovarian Syndrome (PMOS)-Associated Infertility.
From mitochondria to innate immunity: The mtDNA-driven cGAS/STING-NLRP3 cascade and its therapeutic implications in neurodegenerative diseases (Review).
Hesperetin Attenuates Experimentally Induced Skeletal Muscle Dysfunction by Modulating Time-of-Day-Dependent Gene Expression and Mitochondrial Redox-Related Markers.
White Wine Intake Reduces Mitochondrial Complex I-Derived ROS in the Male Rat Heart.
Mitophagy's impact on obesity-related tissues.
Impact of green tea on obesity-related hormones in postmenopausal women: A systematic review and meta-analysis of randomized controlled trials.
Dietary Nucleotides as Potential Modulators of Inflammatory and Metabolic Pathways with Implications for Insulin Resistance.
Zingerone mitigates cognitive and motor impairments in a D-galactose-induced brain aging model: Role of oxidative stress and neuroinflammation.
Antioxidant Interventions on Muscle Function and Mass in Aging-Related Muscle Decline: A Systematic Review of Preclinical and Clinical Evidence.
Prohibitin 2 mediates the mitochondrial protective effect of the whey-derived tetrapeptide Gly-Thr-Trp-Tyr.
Aging patterns based on the difference between physical fitness age and chronological age are associated with physical, mental, and cognitive health in older adults.
Effects of Protocatechuic Acid on Endothelial Function and HDL Functionality in Hypercholesterolemic Subjects: A Randomized Double-Blind Placebo-Controlled Trial.
Natural-Product-Derived Antioxidants and DNA Methylation-Based Epigenetic Aging: A Systematic Review of Human Intervention Studies.
Nobiletin as a Geroprotective Flavonoid: Mechanisms of Action, Therapeutic Potential, and Challenges of Bioavailability.
Brain energy metabolism in neurodegenerative disease.
Blood biomarkers of oxidative stress and mitochondrial dysfunction in Parkinson's disease and Alzheimer's disease.
Inotodiol prevents age-related muscle wasting by restoring mitochondrial function through liver X receptor beta signaling.
Modulating Ubiquinone Biosynthesis Rescues Mitochondrial Dysfunction by Genetic Interaction in a Phosphatidylethanolamine (PE)-Deficient Disease Model.
Effects of dietary nitrate on cardiovascular reactivity in normotensive postmenopausal women.

Aging Cell. 2026 Oct;25(10): e70729

Mitochondrial Fusion and Fission in Age-Related Cardio-Cerebral Diseases: Mechanisms and Interventions.

Yuyao Yin, Zijian Li.

  Mitochondria play a crucial role in cellular energy metabolism. The heart and brain require a continuous and stable energy supply. Energy production strongly depends on proper mitochondrial function. Mitochondrial fusion and fission, known as "plasticity", are vital for maintaining the normal physiological function of cells. Recent studies have shown that impaired mitochondrial dynamics are present in many aging-related diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and atherosclerotic cardio-cerebrovascular disease. The role of impaired mitochondrial dynamics in the pathophysiological process of aging-related diseases is being actively researched. We discovered that targeting proteins related to mitochondrial dynamics, especially those involved in fission and fusion, may offer new treatment strategies for these diseases. Various approaches, including aerobic interval and treadmill training and the use of drugs such as the antidiabetic agents metformin and dapagliflozin, the antihypertensive agent irbesartan, and certain traditional Chinese medicine components, have shown potential in alleviating imbalances in mitochondrial dynamics in aging-related cardio-cerebrovascular diseases. In this review, we systematically summarize recent research on alterations in mitochondrial dynamics in age-related cardio-cerebral diseases and explore therapeutic strategies targeting these alterations, which may offer new directions for improving cardiac and brain health and guiding clinical practice.

Keywords:  age‐related disease; cardiovascular disease; fission and fusion; mitochondrial dynamics; neurodegenerative disease

DOI:  https://doi.org/10.1111/acel.70729
Biology (Basel). 2026 Sep 08. pii: 1573. [Epub ahead of print]15(18):

SIRT1 in Senescence: Mitochondria and Immune Crosstalk.

Jirapat Namkaew, Pornparn Kongpracha, Tanakamol Mahawan, Thiranut Jaroonwitchawan.

  Cellular senescence is one of the hallmarks of aging. These growth-arrested cells actively secrete inflammatory mediators that reshape the tissue microenvironment and fuel age-related pathology. Sirtuin 1 (SIRT1) is an NAD+-dependent deacetylase that regulates senescence largely through its control over mitochondrial integrity and inflammatory signaling. SIRT1 levels and activity fall with age, and this decline directly promotes senescence. SIRT1 maintains mitochondrial function through three interconnected pathways: PGC-1α-driven mitochondria biogenesis, FOXO-dependent antioxidant defense, and mitophagic clearance of damaged organelles. When SIRT1 activity is in an unsteady state, mitochondria become unhealthy. This leads to excessive ROS generation and the leakage of mitochondrial DNA (mtDNA) into the cytosol, which activates the innate immune pathway, consequently resulting in the production of inflammatory cytokines that further inhibit SIRT1. This self-amplifying loop drives cells to irreversible senescence. In this study, we integrate the current understanding of the SIRT1-mitochondria-immune axis within the framework of senescence by examining the biological roles of SIRT1 and the mechanisms that lead to its reduction with aging, while also exploring the interrelated mitochondrial pathways and inflammatory signaling. Furthermore, we assess possible therapeutic strategies targeting this axis and highlight essential questions that necessitate additional research.

Keywords:  SASP; SIRT1; aging; cellular senescence; mitochondria; mitophagy

DOI:  https://doi.org/10.3390/biology15181573
Nat Med. 2026 Sep 22.

Blood proteomics of menopause map to brain aging and dementia risk.

Madeline Wood Alexander, Jennifer S Rabin, Michelle Caunca, Allesandra Iadipaolo, Louisa Cornelis, Ria Warrier, Keenan A Walker, Nina Miolane, Veronica Augustina Bot, Brendan Wood, Hamilton Se-Hwee Oh, Tony Wyss-Coray, Albert Pham, Julia Borger, Valentina Diaz, Emily W Paolillo, Joel Kramer, Laura Pritschet, Caitlin Taylor, Matthew S Panizzon, Ramiro Eduardo Rea Reyes, Marisa N Denkinger, Nicholas J Ashton, Sterling C Johnson, Emily G Jacobs, Rowan Saloner, Kaitlin B Casaletto.

Menopause is a hallmark process in biological aging that has been implicated in later neurodegenerative risk, but the pathways underlying this connection remain unclear. Here we used blood proteomics data from several cohorts to identify biological changes associated with menopause and its links to brain aging. In n = 80 rigorously staged (STRAW+10) pre-, peri- and postmenopausal women (aged 43-58 years) with serum NULISAseq proteomics, we show that spontaneous menopause is characterized by dysregulation in inflammatory, synaptic, metabolic and Alzheimer's disease biologic processes, which tracked more strongly with hormones than with age. Validation analyses in age-matched pre-/peri- and postmenopausal women (n = 2,814) with plasma Olink proteomics replicated the observed proteomic shifts and revealed broader menopause-related upregulation of inflammatory and catabolic processes plus accelerated organ and cell aging, including brain aging. In four independent cohorts of older women (average age, 60.7-72.1 years; total n = 11,925), higher menopause proteomic scores associated consistently with cognitive aging and dementia risk. The molecular signatures of menopause may inform the selection of biomarkers or therapeutic targets for brain health in midlife women.

DOI: https://doi.org/10.1038/s41591-026-04648-4
J Nutr Health Aging. 2026 Sep 23. pii: S1279-7707(26)00224-1. [Epub ahead of print]30(11): 100991

Association of plasma growth differentiation factor 15 with wake after sleep onset in mild cognitive impairment.

Teruaki Masuda, Takuya Ataka, Kaori Sumi, Yosuke Takeuchi, Yuko Akiyoshi, Fusa Matsuzaki, Hirofumi Hirakawa, Etsuro Matsubara, Noriyuki Kimura.

   OBJECTIVES: Circulating growth differentiation factor 15 (GDF-15) concentrations increase with age and are elevated in chronic diseases, but evidence regarding habitual wake after sleep onset (WASO) and circulating GDF-15 remains limited. We therefore examined the cross-sectional association between plasma GDF-15 and wearable-estimated WASO in older adults with mild cognitive impairment (MCI).
DESIGN: Cross-sectional biomarker analysis of first-year data from a prospective community-based cohort.
SETTING: USUKI study, Usuki, Oita, Japan.
PARTICIPANTS: 118 community-dwelling adults aged ≥65 years with MCI.
INTERVENTION: None.
MEASUREMENTS: We measured plasma GDF-15 concentrations using an enzyme-linked immunosorbent assay. We averaged wearable sleep data across repeated assessments. WASO was the primary measure of sleep continuity; total sleep time (TST) was examined as a measure of sleep quantity; and amyloid burden was assessed using 11C-Pittsburgh compound B PET (PiB-PET) global standardized uptake value ratio (SUVR) and PiB positivity.
RESULTS: The median plasma GDF-15 concentration was 1,230.8 pg/mL (IQR, 956.6-1,590.5), and the median WASO was 18.4 min (IQR, 11.6-27.5). After adjustment for age, sex, education, diabetes mellitus, and estimated glomerular filtration rate, each 10-min increment in WASO was associated with a 10.6% higher GDF-15 concentration (95% CI, 4.8%-16.8%; p < 0.001). TST and PiB-PET global SUVR were not significantly associated with GDF-15, and the proportion of PiB-positive participants did not differ across GDF-15 tertiles.
CONCLUSION: In older adults with MCI, poorer habitual nocturnal sleep continuity, as reflected by greater wearable-estimated WASO, was associated with higher plasma GDF-15 concentrations after multivariable adjustment.

Keywords:  Growth differentiation factor 15; Mild cognitive impairment; Sleep continuity; Wake after sleep onset; Wearable device

DOI:  https://doi.org/10.1016/j.jnha.2026.100991
Geroscience. 2026 Sep 23.

Ketone ester supplementation in aged mice produces sex-specific cognitive and metabolic effects.

Kirsten J Roslund, Laurynne C Coates, Sadia Sattar Sultani, Dylan Hayes, Samantha Diaz, Jennifer M Rutkowsky, Zeyu Zhou, Jon J Ramsey, Ameer Y Taha, Carolyn M Slupsky.

  The ketogenic diet (KD) elevates β-hydroxybutyrate (β-HB), an energy metabolite and signaling molecule with immunomodulatory effects, and has been associated with cognitive and metabolic effects in some preclinical and clinical studies. However, clinical evidence for ketogenic and ketone-based interventions in cognitive aging and Alzheimer's disease remains mixed, and long-term carbohydrate restriction may be difficult to implement in older adults. Dietary supplements that elevate β-HB, such as medium-chain triglycerides and ketone esters, have been proposed as alternatives to the KD, but their sex-specific effects in aging remain poorly defined. Here, we determined the effects of short-term supplementation with the ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate on physical function, metabolism, and age-related memory outcomes in 24-month-old male and female C57BL/6 mice. The ketone ester-containing diet increased postprandial β-HB and lowered postprandial glucose; however, its effects on cognitive, anthropometric, inflammatory, and metabolic outcomes differed by sex. In males, the intervention changed body composition, with lower body fat and higher relative lean mass. In females, the intervention was associated with fewer Barnes maze primary errors and lower hippocampal IL-1β expression. These sex-dependent effects were accompanied by differences in fasting metabolite profiles across tissues and biofluids and by altered hippocampal oxylipins. Further studies are needed to determine whether ketone monoester supplementation has similar sex-specific effects in humans, and to define the mechanisms, physiological changes, and translational relevance of ketone-based interventions in aging.

Keywords:  Aging; Cognition; Ketogenic; Ketone; Ketone ester; β-hydroxybutyrate

DOI:  https://doi.org/10.1007/s11357-026-02546-8
Antioxidants (Basel). 2026 Sep 10. pii: 1152. [Epub ahead of print]15(9):

Oxidative Stress in Vascular Aging: Therapeutic Potential of the Antioxidant Paradox. A State-of-the-Art Review.

Aleyma Veliz Perez, Mihaela Badea, Sehrish Bilal.

  Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, with aging as one of its main risk factors. Cellular senescence and oxidative stress form a bidirectional vicious cycle that drives vascular aging, endothelial dysfunction, and atherosclerotic progression. This state-of-the-art review synthesizes current evidence on the interplay between oxidative stress and senescence in cardiovascular aging and critically assesses whether antioxidant strategies can benefit vascular health. A targeted literature search was conducted in PubMed/MEDLINE, Web of Science, and Scopus (2016-2026). While endogenous antioxidant defenses decline with age, exogenous antioxidants, including resveratrol, vitamins C and E, omega-3 fatty acids, carotenoids, and coenzyme Q10,demonstrate promising preclinical effects, yet large-scale clinical trials have yielded inconsistent results. The VITAL and STRENGTH trials failed to demonstrate significant cardiovascular benefit with omega-3 supplementation, and elevated serum β-carotene was found paradoxically associated with increased cardiovascular mortality. Emerging mitochondria-targeted antioxidants (MitoQ, MitoTEMPO) show preclinical promise but require further clinical validation. Current evidence does not support antioxidant supplementation for cardiovascular prevention. Lifestyle interventions, particularly antioxidant-rich dietary patterns such as the Mediterranean diet, remain the safest strategy. Future research should develop personalized approaches guided by oxidative stress biomarkers and long-term trials.

Keywords:  aging; antioxidants; cardiovascular; oxidative stress; vascular health

DOI:  https://doi.org/10.3390/antiox15091152
Int J Womens Health. 2026 ;18 619132

Evaluating the Therapeutic Potential of Antioxidants in Polyendocrine Metabolic Ovarian Syndrome (PMOS)-Associated Infertility.

Pramathes Das Mahapatra, Vidya Vishwanath Bhat, Noopur Ajaykumar Vyas, Shruti Dharmadhikari, Gaurav Puppalwar, Chintan Khandhedia, Amey Mane, Suyog Mehta.

   Introduction: Polyendocrine Metabolic Ovarian syndrome (PMOS) formerly known as polycystic ovarian syndrome (PCOS) constitutes the most common endocrinopathy in women of reproductive age group. Evidence from numerous studies in PMOS patients suggests that antioxidants can modulate the ovarian microenvironment, promote folliculogenesis, and increase oocyte competence and yield. This review aims to summarize the existing clinical evidence regarding the application of antioxidants as adjunctive treatment options in the management of PMOS-related infertility.
Materials and Methods: This is a structured narrative review. A literature search (1990-2024) was conducted through PubMed, Google Scholar, and Cochrane Library to identify clinical trials evaluating the role of antioxidants specifically Coenzyme Q10 (CoQ10), N-acetylcysteine (NAC), melatonin, and astaxanthin (AST) in PMOS. Studies were identified and screened based on the predefined eligibility criteria. Inclusion criteria were full-text, English-language studies assessing antioxidant interventions in PMOS or related mechanisms; exclusions were reviews, meta-analyses, animal studies, duplicates, and non-English articles. Of 198 records screened, 28 studies met eligibility criteria and were included in this review.
Results: Based on the data included in our review, the available evidence suggests that CoQ10 enhances mitochondrial function and reduces oxidative stress (OS). It has been reported to increase clinical pregnancy rates, improve insulin sensitivity, sex hormone levels, and blood lipids. N-acetylcysteine scavenges free radicals, provides cysteine for glutathione synthesis, breaks disulfide linkages and reduces OS. It may help to improve pregnancy rates, insulin sensitivity, and metabolic parameters. Additionally, it enhances oocyte quality and supports detoxification. Astaxanthin is a potent antioxidant with anti-inflammatory properties and reduces OS, with the potential to improve the development of follicles and oocytes, insulin sensitivity, lipid parameters, and supports mitochondrial health and cellular function. Melatonin regulates circadian rhythms and reduces OS, helps restore regular menstrual cycles, reduces hyperandrogenism, may improve insulin sensitivity and enhance fertility.
Conclusion: Antioxidant supplementation may have a complementary role in improving reproductive outcomes in infertile women with PMOS. However, some uncertainty remains given the heterogeneity of the included studies and the limited number of trials for certain antioxidants. Further well-designed randomized controlled studies are required to establish definitive clinical benefit.

Keywords:  PMOS; antioxidants; astaxanthin; coenzyme Q10; infertility; melatonin; n-acetyl cysteine; polycystic ovary syndrome

DOI:  https://doi.org/10.2147/IJWH.S619132
Exp Ther Med. 2026 Oct;32(4): 291

From mitochondria to innate immunity: The mtDNA-driven cGAS/STING-NLRP3 cascade and its therapeutic implications in neurodegenerative diseases (Review).

Hui Liu, Yao Zhang, Ziliang Zhuo, Wei Zhong, Manyun Yan, Zhongbo Zhao.

  Neurodegenerative diseases (NDDs) are commonly accompanied by persistent low-grade neuroinflammation, yet current therapies rarely achieve durable disease modification. This review aims to systematically delineate the role of mitochondrial DNA (mtDNA) leakage in linking mitochondrial injury to innate immune activation and to explore its pathological significance in NDDs. A comprehensive review of recent literature on mitochondrial stress, mtDNA release and innate immune signaling was conducted. Evidence was integrated regarding the sources of mtDNA immunogenicity, routes of mtDNA escape, mitophagy-lysosome gating mechanisms and the modulation of leakage baseline by aging and metabolic stress. Accumulating evidence indicates that cytosolic mtDNA is sensed by cyclic GMP-AMP synthase (cGAS) and activates the stimulator of interferon (IFN) genes (STING) pathway signaling through the TANK-binding kinase 1 and IFN regulatory factor 3 axis to induce type I IFN responses and promoting NF-κB-driven inflammatory transcription, thereby enhancing NLRP3 inflammasome priming. Oxidized mtDNA, pore-forming membrane events and ionic imbalance further facilitate NLRP3 assembly and pyroptotic execution, exacerbating mitochondrial damage and mtDNA release in a self-amplifying loop. Based on these findings, a modular assessment framework was proposed across the 'input-chronicity-amplification' layers and the potential of mtDNA-cGAS/STING-NLRP3 axis-informed stratified diagnosis and treatment was discussed Central nervous system-targeted delivery, cellular heterogeneity and immune safety windows remain critical for translational research. This review provides a testable mechanistic framework and a clinical evaluation pathway for understanding mtDNA-driven persistent inflammation in NDDs.

Keywords:  NLRP3 inflammasome; cGAS/STING; mtDNA; neuroinflammation; stratified assessment

DOI:  https://doi.org/10.3892/etm.2026.13286
Antioxidants (Basel). 2026 Sep 17. pii: 1185. [Epub ahead of print]15(9):

Hesperetin Attenuates Experimentally Induced Skeletal Muscle Dysfunction by Modulating Time-of-Day-Dependent Gene Expression and Mitochondrial Redox-Related Markers.

Suhyeon Lee, Yumin Sim, Minkyeong Lee, Eunju Kim.

  Skeletal muscle aging is characterized by impaired myogenic differentiation, mitochondrial dysfunction, oxidative stress, and circadian rhythm disruption, contributing to sarcopenia and muscle atrophy. Hesperetin, a natural flavonoid, has antioxidant and mitochondrial protective effects; however, its role in skeletal muscle circadian regulation during aging remains unclear. This study investigated the effects of hesperetin (20 µM or 100 mg/kg b.w.) using D-galactose (D-gal, 20 g/L)-induced senescent C2C12 myotubes, a D-gal (150 mg/kg b.w., i.p.)-induced aging mouse model, and a dexamethasone (Dex, 20 mg/kg b.w., i.p.)-induced muscle atrophy model. In D-gal-treated mice, hesperetin improved hanging test performance and increased SDH-positive area, particularly during the active phase. Hesperetin also partially modulated core clock gene expression and mitochondrial function-related gene expression. In D-gal-induced senescent C2C12 myotubes, hesperetin improved myotube formation, reduced SA-β-gal-positive cells, DCF-DA fluorescence, and MDA levels, enhanced antioxidant enzyme activities, and improved mitochondrial-associated functional indicators, including ATP levels, mitochondrial membrane potential-related fluorescence, pMitoTimer-based mitochondrial oxidation-associated signals, and Ppargc1a expression patterns. These findings suggest that hesperetin may protect against experimentally induced skeletal muscle dysfunction by modulating time-dependent gene expression, mitochondrial-related activities, and muscle-related functional markers.

Keywords:  circadian rhythm; hesperetin; mitochondrial function; oxidative stress; skeletal muscle aging

DOI:  https://doi.org/10.3390/antiox15091185
Antioxidants (Basel). 2026 Sep 19. pii: 1199. [Epub ahead of print]15(9):

White Wine Intake Reduces Mitochondrial Complex I-Derived ROS in the Male Rat Heart.

Jeronim Matijevic, Marko Grahovac, Marin Mornar, Ivana Novak, Marko Ljubkovic, Mladen Boban, Jasna Marinovic.

  Epidemiological studies suggest that, despite the adverse effects of excessive alcohol intake, low-to-moderate levels of wine consumption have been associated with favorable cardiovascular outcomes. While the biological effects of polyphenol-rich red wine have been extensively studied, less is known about the impact of white wine on myocardial cellular function and the underlying mechanisms. In this study, young male Sprague-Dawley rats were given ad libitum access to white wine or water for four weeks, after which cardiac mitochondrial function, cardiomyocyte susceptibility to oxidative stress, and cardiac transcriptomic profiles were assessed using respirometry, ROS measurements, in vitro oxidative stress assay, and RNA sequencing. White wine consumption did not significantly alter mitochondrial respiratory capacity, expression of antioxidant enzymes or cardiomyocyte survival following oxidative challenge. However, mitochondrial ROS production at respiratory complex I was significantly reduced, particularly during reverse electron transport mimicking ischemia/reperfusion. Transcriptomic analysis revealed modest changes, with no genes meeting the false discovery rate threshold. Analyses based on nominal significance revealed changes associated with mitochondrial electron transfer, protein quality control, apoptosis, and inflammatory signaling. In conclusion, four-week white wine consumption was associated with reduced mitochondrial ROS without impairing cardiac bioenergetics, accompanied by subtle transcriptional responses.

Keywords:  ischemia/reperfusion; myocardial mitochondria; reactive oxygen species; transcriptomics; white wine

DOI:  https://doi.org/10.3390/antiox15091199
Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(25)00166-2. [Epub ahead of print]406 87-130

Mitophagy's impact on obesity-related tissues.

Rana El Nahas, Sandra Cutanda-Tesouro, Meritxell Espino-Guarch, Pablo M Garcia-Roves.

  Obesity, a global health crisis, results from an energy imbalance, leading to metabolic dysfunction and associated conditions such as type 2 diabetes, cardiovascular disease, and metabolic dysfunction-associated steatotic liver disease. A strong link exists between obesity and mitochondrial dysfunction, characterized by reduced mitochondrial mass, impaired oxidative capacity, and decreased ATP production. Mitophagy, a specific type of autophagy targeting mitochondria for degradation, plays a complex, tissue-specific role in regulating metabolism and mitigating the harmful effects of obesity. Both insufficient and excessive mitophagy can negatively influence disease progression. In white adipose tissue, mitophagy functions as a quality control mechanism that reduces oxidative stress and helps maintain insulin sensitivity. However, chronic obesity impairs mitophagy due to overactivation of mTORC1 and inhibition of AMPK, leading to inflammation and insulin resistance. In brown adipose tissue, mitophagy is essential for thermogenesis and energy expenditure, but excessive activation in obesity may impair thermogenesis. In the liver, mitophagy is crucial for preserving mitochondrial function and preventing metabolic dysfunction-associated steatotic liver disease. In the heart, mitophagy supports cardiac function, particularly in obesity-related cardiomyopathy. In skeletal muscle, obesity worsens impairments in mitochondrial quality control, disrupting the clearance of damaged mitochondria. Therefore, there is a pressing need for therapies that restore mitophagic balance in a context- and depot-specific manner, as the dysregulation of mitophagy contributes not only to local dysfunction but also to broader metabolic phenotypes.

Keywords:  autophagy; mitochondria and metabolic dysfunction; mitophagy; obesity

DOI:  https://doi.org/10.1016/bs.ircmb.2025.12.003
Avicenna J Phytomed. 2026 ;16(5): 819-833

Impact of green tea on obesity-related hormones in postmenopausal women: A systematic review and meta-analysis of randomized controlled trials.

Sahar Ghoflchi, Hossein Hosseini, Sajad Rafiee, Ghader Babaei, Majid Effati, Mahdieh Aliyari, Reyhane Ghavour Vatanparast, Masoud Imani, Masoumeh Rajabibazl.

   Objective: Menopause leads to hormonal changes that increase visceral fat, raising risks for metabolic disorders and breast cancer due to altered adipocytokine levels. Green tea (Camellia sinensis L.), containing catechins like EGCG (epigallocatechin gallate), may improve metabolic health in postmenopausal women. In this review we assessing the effects of green tea consumption on key obesity related hormones in postmenopausal women.
Materials and Methods: This study reviewed randomized controlled trials (RCTs) from PubMed, Science Direct, Cochrane Library, and Google Scholar up to March 2024, focusing on green tea's effects on leptin, adiponectin, ghrelin, and insulin. Eight RCTs with 632 participants were analyzed using standardized mean differences (SMDs) with 95% confidence intervals (CIs) in a random-effects model. Heterogeneity was measured with the I2 statistic, and publication bias was assessed via Egger's test and funnel plots.
Results: Green tea significantly reduced ghrelin levels (SMD: -4.63, 95% CI: -8.44 to -0.82, p = 0.02, I2 = 98.98%), particularly at doses >1000 mg/day and durations >8 weeks. No significant effects were observed for leptin (SMD: -0.33, 95% CI: -0.89 to 0.22, p = 0.24), adiponectin (SMD: -0.53, 95% CI: -1.44 to 0.39, p = 0.26), or insulin (SMD: -0.87, 95% CI: -4.31 to 2.58, p = 0.62). Subgroup analyses revealed significant reductions in leptin at doses >1000 mg/day, durations ≤8 weeks, and BMI <29 kg/m2; adiponectin at 400-1000 mg/day and insulin at durations ≤8 weeks and BMI <29 kg/m2. High heterogeneity and some evidence of publication bias were noted.
Conclusion: Green tea notably reduced ghrelin, with context-specific effects on leptin, adiponectin, and insulin based on dose, duration, and body mass index (BMI), suggesting tailored benefits for postmenopausal women's metabolic health.

Keywords:  Adiponectin; Ghrelin; Green tea; Insulin; Leptin; Postmenopause

DOI:  https://doi.org/10.22038/ajp.2025.26841
Int J Mol Sci. 2026 Sep 12. pii: 8133. [Epub ahead of print]27(18):

Dietary Nucleotides as Potential Modulators of Inflammatory and Metabolic Pathways with Implications for Insulin Resistance.

Renata Karaś, Urszula E Binduga, Konrad A Szychowski.

  Dietary nucleotides and nucleic-acid-derived compounds are considered bioactive nutrients, but their metabolic relevance remains uncertain. This narrative review, supported by a structured literature search, evaluates intestinal handling and evidence on glucose and lipid metabolism, redox homeostasis, immune function, gut barrier regulation, and microbiota. Direct supplementation studies are distinguished from nucleoside/nucleobase evidence, dietary nucleic acids or purine-rich foods, and endogenous extracellular purinergic signaling. Preclinical studies suggest defined nucleotide preparations may modulate AMP-activated protein kinase (AMPK), insulin receptor substrate 1 (IRS-1)/protein kinase B (AKT)/forkhead box protein O1 (FOXO1) signaling, lipid accumulation, and mitochondrial/redox-related endpoints. In contrast, extracellular adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine 5'-monophosphate (AMP) studies provide mechanistic context but do not show that oral supplementation modifies purinergic signaling in humans. Human intervention evidence is sparse and derived from older adults not selected for insulin resistance, type 2 diabetes, or metabolic-dysfunction-associated steatotic liver disease (MASLD). Reductions in homeostatic model assessment of insulin resistance (HOMA-IR) should be interpreted as changes in a surrogate estimate, not proof of therapeutic efficacy. The supplemental doses evaluated in available human intervention studies appear generally well-tolerated, whereas short-term high nucleotide intake can raise circulating uric acid. Dietary nucleotides therefore remain candidate, not established, metabolic or immune therapies.

Keywords:  dietary nucleotides; insulin resistance; oxidative stress

DOI:  https://doi.org/10.3390/ijms27188133
Mol Biol Rep. 2026 Sep 22. pii: 1607. [Epub ahead of print]53(1):

Zingerone mitigates cognitive and motor impairments in a D-galactose-induced brain aging model: Role of oxidative stress and neuroinflammation.

Ali Reza Malayeri, Mohsen Zand, Sirous Rafiei Asl, Mohammadreza Rashidi-Nooshabadi, Seyed Esmaeil Khoshnam.

   BACKGROUND: The use of natural compounds with potent antioxidant and anti-inflammatory properties is a key strategy against age-related neurobehavioral deficits. This study investigated the protective effects of Zingerone (ZIN) and its underlying mechanisms against D-galactose (D-gal)-induced brain aging, with a focus on oxidative stress, inflammatory markers, and neurobehavioral deficits.
MATERIAL AND METHODS: Male Wistar rats were divided into five groups: a control group (normal saline), a D-gal group (100 mg/kg), and three ZIN treatment groups (5, 10, and 20 mg/kg). An aging model was induced by daily subcutaneous injection of D-gal for eight weeks. Concurrently, the ZIN treatment groups received their respective doses by daily gavage over the same eight-week period. We evaluated the cognitive and locomotor functions of the animals using standard behavioral tests including Morris water maze (MWM), passive avoidance task (PAT), open field test (OFT) and rotarod test. In addition, we assessed the oxidative-antioxidative status and inflammatory conditions in the hippocampus, and conducted a qualitative histopathological evaluation of the hippocampal tissue and cortex of the experimental rats.
RESULTS: Our findings indicate that ZIN treatment significantly enhanced cognitive and motor function and reduced oxidative stress and neuroinflammation in the hippocampus, as well as attenuate histopathological changes in the cortex and hippocampal areas of D-gal-induced brain aging rats. These effects were dose-dependent, and the most protective effects were demonstrated at the 20 mg/kg dosage. A significant association between oxidative stress markers, inflammatory cytokines, and cognitive functions was confirmed by correlation analyses.
CONCLUSION: This study demonstrates that ZIN protects against D-gal-induced cognitive and motor deficits by enhancing antioxidant and anti-inflammatory activity in the hippocampus. These findings support the potential of ZIN as a natural compound with therapeutic and health benefits for improving age-related neurobehavioral decline.

Keywords:  Aging; D-galactose; Histopathological; Neuroinflammation; Oxidative stress; Rat; Zingerone

DOI:  https://doi.org/10.1007/s11033-026-12748-0
Antioxidants (Basel). 2026 Sep 15. pii: 1167. [Epub ahead of print]15(9):

Antioxidant Interventions on Muscle Function and Mass in Aging-Related Muscle Decline: A Systematic Review of Preclinical and Clinical Evidence.

Xin Li, Ke Zhou, Ronald Man Yeung Wong, Wing Hoi Cheung, Can Cui.

  Oxidative stress contributes to aging-related muscle decline, but antioxidant interventions may affect functional and structural outcomes differently. This systematic review synthesized clinical, animal, and cellular evidence across clinically defined sarcopenia and broader models of aging-related muscle decline. PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched through 11 July 2026. Eligible studies tested antioxidant interventions in older adults or aging-related preclinical models and were appraised using the Cochrane Risk of Bias 2 (RoB 2) tool, a modified Systematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk-of-bias tool, and a modified in vitro checklist. Forty-four publications were included: eight clinical trials, 26 animal datasets, and 18 cellular datasets, with eight publications contributing both animal and cellular evidence. Comparative clinical benefits were reported primarily for strength or power (7/8 studies), with less support for physical performance (2/6 studies assessing this domain) or body composition-related muscle quantity (2/8 studies). Selected preclinical studies likewise showed functional gains without parallel structural improvement, although effects varied by model and intervention. Preclinical findings implicated antioxidant defense, mitochondrial maintenance, inflammation, and proteostasis, but most pathway evidence was associative and direct experimental validation was limited. Clinical evidence was further constrained by small samples, short interventions, combined nutritional or exercise co-interventions, and heterogeneous outcomes. Current evidence does not support a consistent increase in muscle quantity with antioxidant interventions. The observed pattern appears context dependent and requires confirmation in adequately powered, phenotype-stratified trials assessing muscle strength, physical performance, muscle quantity, and mechanistic endpoints.

Keywords:  aging; aging-related muscle decline; antioxidants; mitochondrial dysfunction; oxidative stress; sarcopenia; systematic review

DOI:  https://doi.org/10.3390/antiox15091167
Biochem Biophys Res Commun. 2026 Sep 21. pii: S0006-291X(26)01375-6. [Epub ahead of print]837 154609

Prohibitin 2 mediates the mitochondrial protective effect of the whey-derived tetrapeptide Gly-Thr-Trp-Tyr.

Noa Mizukami, Kotoha Miwa, Kentaro Umeda, Takafumi Fukuda, Naoharu Takano, Masaki Hiramoto.

  Certain dairy products have been reported to reduce the risk of cognitive decline in older adults and patients with Alzheimer's disease (AD). Intake of the whey-derived tetrapeptide Gly-Thr-Trp-Tyr (GTWY) improves mild cognitive impairment in healthy adults, while GTWY administration in mice suppresses AD-like pathologies, including amyloid-beta (Aβ) accumulation and neuroinflammation. GTWY treatment also reduces Aβ-induced mitochondrial dysfunction in neuronal cells. However, the molecular mechanisms underlying these effects remain unclear. Here, we identified prohibitin 2 (PHB2) as a direct binding partner of GTWY in human neuroblastoma SH-SY5Y cells and investigated its role in the mitochondrial protective effect of GTWY. GTWY treatment increased the abundance of the prohibitin complex detected by blue native PAGE without affecting PHB1 or PHB2 expression. Moreover, PHB2 knockdown abolished the mitochondrial protective effect of GTWY, indicating that PHB2 mediates this effect. These findings suggest that GTWY binding to PHB2 modulates the functional state of the prohibitin complex, thereby preserving mitochondrial function. Our results provide new insights into the molecular mechanisms underlying the mitochondrial protective effects of whey-derived peptides and highlight the potential role of the prohibitin complex in mediating these effects.

Keywords:  Mild cognitive impairment; Mitochondria; Molecular target; Prohibitin; Whey-derived peptide

DOI:  https://doi.org/10.1016/j.bbrc.2026.154609
Geriatr Nurs. 2026 Sep 24. pii: S0197-4572(26)00563-X. [Epub ahead of print]74(Pt A): 104358

Aging patterns based on the difference between physical fitness age and chronological age are associated with physical, mental, and cognitive health in older adults.

Kening Xue, Chuanwei Pan, Lei Yang, Hairong Wang, Xiaoguang Zhao.

   PURPOSE: This study examined the association between aging patterns, based on the physical fitness age (PFA) and chronological age (CA) discrepancy, and multidimensional health in 2207 older Chinese adults (aged ≥60 years).
METHODS: PFA was derived using sex-stratified regression equations integrating peak expiratory flow, handgrip strength, walking speed, 5-time chair stand test, and CA, with participants categorized into decelerated (PFA-CA < -2.5 years), normal (-2.5 to +2.5 years), or accelerated (PFA-CA > +2.5 years) aging groups.
RESULTS: Multivariable logistic regression models were performed. The results demonstrated that accelerated aging was associated with higher odds of relevant depressive symptoms (aOR = 1.88, 95% CI: 1.22, 2.90) and cognitive impairment (aOR = 1.76, 95% CI: 1.11, 2.79). Conversely, decelerated aging was significantly linked to higher odds of remaining free from chronic diseases (aOR = 1.77, 95% CI: 1.02, 3.07), though no significant cognitive or depression advantages were observed compared to normal aging. Further analysis identified a significant PFA × Sex interaction for cognitive impairment (p = 0.001), with the cognitive association strongly driven by females (aOR = 3.99, 95% CI: 2.20, 7.20).
CONCLUSION: These findings suggest that aging patterns defined by the PFA-CA discrepancy are associated with chronic, cognitive, and mental health, and older females exhibit heightened cognitive vulnerability to accelerated physical aging.

Keywords:  Age factors; Aging; Cognitive; Depression; Physical fitness

DOI:  https://doi.org/10.1016/j.gerinurse.2026.104358
Nutrients. 2026 Sep 18. pii: 3056. [Epub ahead of print]18(18):

Effects of Protocatechuic Acid on Endothelial Function and HDL Functionality in Hypercholesterolemic Subjects: A Randomized Double-Blind Placebo-Controlled Trial.

Guanyu Chen, Yihan Wang, Qiuhui Xu, Ruxun Zhao, Yihao Yuan, Dongliang Wang.

  Background: High-density lipoprotein (HDL) exerts atheroprotective properties, partially by maintaining endothelial function. Protocatechuic acid (PCA) has been shown to improve endothelial function in mice. However, whether PCA improves endothelial function in humans is currently unknown. Our studies aimed to evaluate the effects of PCA on endothelial function and HDL concentration, subclass distribution, and functionality in humans. Methods: A double-blind, randomized, placebo-controlled trial was conducted in 150 hypercholesterolemic participants (aged 35-65 y) daily receiving 20 mg PCA or placebo capsules for 12 weeks. Endothelial function [brachial artery flow-mediated dilation (FMD)], serum cyclic guanosine monophosphate (cGMP), HDL concentration, subclass distribution (pre-β-HDL, HDL3, HDL2), and functionality [endothelial nitric oxide synthase (eNOS) activity] were tested at baseline, 6 weeks, and 12 weeks. Results: PCA consumption for 12 weeks significantly improved brachial artery FMD [1.77% (95% CI: 1.46 to 2.08)] and increased cGMP [11.72 pmol/L (95% CI: 6.16 to 17.28)] as compared to the placebo treatment, along with increased HDL3, decreased HDL2, and non-significantly changed in HDL and pre-β-HDL. PCA consumption also increased eNOS activity of HDL [0.39 (95% CI: 0.29 to 0.49)]. In the PCA group, the changes in HDL functionality on eNOS activity were positively correlated with the changes in brachial artery FMD, cGMP, and HDL3, whereas negatively correlated with HDL2. Conclusions: PCA consumption improves endothelial function and HDL functionality in humans with hypercholesterolemia, with accompanying shifts in HDL subclass distributions. These findings are hypothesis-generating and require confirmation in larger, long-term trials.

Keywords:  HDL functionality; HDL subclass distribution; endothelial function; endothelial nitric oxide synthase activity; protocatechuic acid

DOI:  https://doi.org/10.3390/nu18183056
Antioxidants (Basel). 2026 Aug 28. pii: 1075. [Epub ahead of print]15(9):

Natural-Product-Derived Antioxidants and DNA Methylation-Based Epigenetic Aging: A Systematic Review of Human Intervention Studies.

Fatemeh Taktaz, Salar Hafez-Ghoran.

  DNA methylation clocks provide a tractable molecular readout for testing whether nutritional and natural-product interventions can modify biological aging. Natural-product-derived antioxidants are biologically plausible candidates because they influence redox signaling, inflammation, mitochondrial function, microbial metabolism and epigenetic regulation, yet their effects on DNA methylation-based aging remain difficult to interpret. Here, we systematically synthesize human intervention studies evaluating antioxidant-rich dietary patterns, botanical and food-derived extracts, marine omega-3 fatty acids, multi-component nutraceuticals and related lifestyle-based interventions with DNA methylation-clock outcomes. The available evidence does not support a uniform epigenetic anti-aging effect. Instead, methylation-age responses were clock-specific, exposure-dependent and often most apparent in metabolically or biologically responsive subgroups. Longer randomized or trial-embedded studies provided the most credible signals, whereas small uncontrolled studies mainly generated hypotheses. Future trials should move beyond claims of epigenetic age reversal and test whether objectively verified natural-product-derived antioxidant exposures produce reproducible, mechanistically linked, and clinically meaningful changes in aging biology.

Keywords:  DNA methylation clock; biological aging; epigenetic aging; natural product-derived antioxidants; nutraceuticals; omega-3 fatty acids; polyphenols

DOI:  https://doi.org/10.3390/antiox15091075
Antioxidants (Basel). 2026 Sep 07. pii: 1129. [Epub ahead of print]15(9):

Nobiletin as a Geroprotective Flavonoid: Mechanisms of Action, Therapeutic Potential, and Challenges of Bioavailability.

Szymon Sip, Anna Gościniak, Niklas Hoede, Min Hein Htike, Hnin Yuzana Khin, Wei-Wei Lai, Hein Htet Naing, Agnieszka Szopa, Judyta Cielecka-Piontek.

  Flavonoids are a diverse group of naturally occurring polyphenolic compounds found in plant-based foods and are known for their broad-spectrum biological activities. Among them, nobiletin, a polymethoxylated flavone derived from citrus peels, has gained attention for its multifaceted role in promoting healthy ageing and mitigating age-related diseases. This review explores the chemical properties, mechanisms of action, therapeutic potential, and challenges related to nobiletin. The focus is placed on its antioxidant, anti-inflammatory, neuroprotective, cardioprotective, and metabolic regulatory effects, as well as its capacity to enhance mitophagy, modulate circadian rhythms, and prevent ferroptosis. Despite promising preclinical results across various models, including in vitro cell lines, C. elegans, and mice, the clinical translation of nobiletin is hindered by poor oral bioavailability, complex extraction, and limited human data. Novel delivery systems, such as nanoemulsions and phospholipid-based carriers, offer potential solutions to enhance its bioavailability. As research advances, nobiletin emerges as a promising candidate for geroprotective therapy, warranting further investigation through well-designed clinical trials to extend healthspan and prevent age-associated pathologies.

Keywords:  bioavailability; cellular senescence; circadian rhythm; geroprotector; geroscience; healthy ageing; inflammaging; mitochondrial dysfunction; mitophagy; nobiletin

DOI:  https://doi.org/10.3390/antiox15091129
Neurobiol Dis. 2026 Sep 23. pii: S0969-9961(26)00360-8. [Epub ahead of print] 107615

Brain energy metabolism in neurodegenerative disease.

Carmen Lahr, Elle Wilson, Melanie Sengupta, Michela Bernini, Alexander Skupin.

  The brain is a highly complex organ composed of diverse, specialized cell types whose coordinated functions underpin cognition and behavior. While extensive research has elucidated neuronal signaling mechanisms, the metabolic interactions between distinct brain cells that sustain energy homeostasis are not yet comprehensively understood. Recently, brain energy metabolism has gained significant attention as a unifying factor in the pathogenesis of neurodegenerative diseases such as Alzheimer's and Parkinson's, potentially opening new avenues for therapeutic development. In this review, we provide an overview of brain energy metabolism, examine its role in neurodegeneration, and highlight current challenges and future perspectives in the field.

Keywords:  Alzheimer's disease; Brain energy metabolism; Mitochondrial dysfunction; Parkinson's disease

DOI:  https://doi.org/10.1016/j.nbd.2026.107615
Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00079-6. [Epub ahead of print]191 27-59

Blood biomarkers of oxidative stress and mitochondrial dysfunction in Parkinson's disease and Alzheimer's disease.

Deepak Kumar, Snehasish Shee, Ashok Kumar Datusalia, Shyam Sunder Sharma.

  Parkinson's disease (PD) and Alzheimer's disease (AD) are the most prevalent neurodegenerative disorders and represent a major global health burden. Despite distinct clinical features, both diseases share key pathogenic mechanisms, particularly oxidative stress and mitochondrial dysfunction, which contribute to neuronal injury and progression. Current diagnostic approaches based on clinical evaluation, neuroimaging, and cerebrospinal fluid (CSF) biomarkers are invasive, costly, and often detect disease only after significant neuronal loss, underscoring the need for minimally invasive, pathway-relevant assays. This chapter reviews blood- and CSF-based biomarker assays reflecting oxidative stress and mitochondrial dysfunction in PD and AD, including lipid peroxidation products, antioxidant capacity, oxidative DNA damage markers, mitochondrial bioenergetic indices, and quality-control proteins. Emerging assay platforms targeting circulating cell-free mitochondrial DNA, mitochondrial-derived vesicles, extracellular vesicle cargo, and regulatory non-coding RNAs are also discussed. The mechanistic relevance of these biomarkers is examined in relation to impaired mitochondrial quality control, disrupted redox homeostasis, defective oxidative phosphorylation, and interactions with disease-defining proteins such as α-synuclein, amyloid-β, and phosphorylated tau. Collectively, these assay-based biomarkers hold promise for early detection, disease monitoring, and therapeutic stratification, although challenges related to standardization, sensitivity, and longitudinal validation remain.

Keywords:  Alzheimer’s disease; Blood biomarkers; Cerebrospinal fluid; Extracellular vesicles; Mitochondrial DNA; Mitochondrial dysfunction; Neurodegeneration; Oxidative stress; Parkinson’s disease

DOI:  https://doi.org/10.1016/bs.irn.2026.07.003
Signal Transduct Target Ther. 2026 Sep 25. pii: 408. [Epub ahead of print]11(1):

Inotodiol prevents age-related muscle wasting by restoring mitochondrial function through liver X receptor beta signaling.

Chang-Lim You, Ju-Hyeon Bae, Yideul Jeong, Young-Eun Leem, June Kim, Jeongmin Park, Tuan Anh Vuong, Jiwoong Jang, Sanghee Park, Young-Sam Lee, Moongi Ji, Man-Jeong Paik, Il-Young Kim, Sang-Jin Lee, Gyu-Un Bae, Jong-Sun Kang.

Sarcopenia is characterized by a progressive decline in muscle mass and strength and represents a major contributor to increased mortality in the elderly population. Mitochondrial dysfunction, which leads to impaired energy metabolism and elevated oxidative stress, is a key driver of muscle wasting and associated metabolic disorders. Thus, mitochondrial targeting is a promising strategy for combating sarcopenia. In this study, we investigated the therapeutic potential of the mycosterol inotodiol (Ino) in mitigating age-related muscle wasting and metabolic dysfunction. Ino treatment significantly improved muscle mass and function in aged mice and prevented dexamethasone (DEX)-induced muscle atrophy. Ino enhanced mitochondrial function and restored muscle metabolism, as evidenced by increased mitochondrial content, elevated oxidative capacity, reduced lipid accumulation, and decreased oxidative stress. In addition, Ino attenuated palmitic acid (PA)-induced lipotoxicity in muscle cells by restoring lipid metabolism. Further investigation revealed that Ino activates liver X receptor β (LXRβ) and promotes its interaction with peroxisome proliferator-activated receptor δ (PPARδ), thereby increasing sirtuin 3 (Sirt3) transcription. Consequently, Ino activates the LXRβ/SIRT3/peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) signaling pathway, a central regulator of mitochondrial function and metabolic homeostasis. Collectively, these findings identify Ino as a promising therapeutic candidate for preserving mitochondrial function and alleviating age-associated muscle dysfunction.

DOI: https://doi.org/10.1038/s41392-026-02935-7
Antioxidants (Basel). 2026 Sep 20. pii: 1212. [Epub ahead of print]15(9):

Modulating Ubiquinone Biosynthesis Rescues Mitochondrial Dysfunction by Genetic Interaction in a Phosphatidylethanolamine (PE)-Deficient Disease Model.

Lavanya Vadupu, Vijay Aditya Mavuduru, Writoban Basu Ball.

  Mitochondrial dysfunctions are often associated with cellular aging as well as metabolic disorders. Therapeutic strategies for rewiring mitochondrial stress signaling in a disease context could be beneficial. New evidence indicates that mitochondrial membrane lipids actively regulate mitochondrial signaling pathways that influence cellular health, stress responses, and longevity. Phosphatidylethanolamine (PE), the non-bilayer-forming phospholipid, plays major roles in mitochondrial morphology and ETC function. The biosynthesis of PE takes place within the inner mitochondrial membrane and is catalyzed by the enzyme phosphatidylserine decarboxylase-1 (PSD-1), which converts phosphatidylserine (PS) to PE. While the biochemical role of PSD-1 in PE biosynthesis is well established, how its dysfunction translates into mitochondrial pathology remains poorly understood. In this work, we describe the physiological implications of PSD-1 function and validate a novel disease model for human PISD (the ortholog of C. elegans psd-1) by undertaking targeted gene knockdown using RNA interference (RNAi) in Caenorhabditis elegans. We show that psd-1 deficiency causes several physiological defects in C. elegans, demonstrating that PE biosynthesis via PSD-1 is critical for mitochondrial activity and organismal development (mitochondrial PE levels were reduced by 69.51% in psd-1 knockdown worms compared to controls). These findings establish psd-1 knockdown worms as a reliable model for studying human PISD-related disease. Surprisingly, co-knockdown of psd-1 along with the ETC component clk-1 rescued physiological defects such as restoring the lifespan of from 13.48 ± 0.51 days psd-1 RNAi worms to 17.36 ± 0.44 days in psd-1; clk-1 double-knockdown worms and normalizing oxygen consumption rate, suggesting that ETC-mediated retrograde signaling, rather than phospholipid depletion alone, is the primary driver of the observed pathology.

Keywords:  Caenorhabditis elegans; DAF-16/FOXO; RNA interference; clk-1; mitochondrial rescue; phosphatidylethanolamine; psd-1; reactive oxygen species; retrograde signaling

DOI:  https://doi.org/10.3390/antiox15091212
Eur J Appl Physiol. 2026 Sep 24.

Effects of dietary nitrate on cardiovascular reactivity in normotensive postmenopausal women.

Maria Lundebrekke, Kathrine Furnes, Michael Vesterlid, Camilla Hatlevoll Nundal, Haakon Kvidaland, Ann-Katrin Grotle.

  Menopause is associated with reduced estrogen and nitric oxide (NO) bioavailability, which may contribute to exaggerated blood pressure (BP) responses (i.e., reactivity) during exercise in postmenopausal women, partly via increased metaboreflex activation. Beetroot juice (BRJ), a source of inorganic nitrate, increases NO bioavailability and has been shown to lower resting BP; however, its effects on BP reactivity in postmenopausal women are less understood. We investigated whether BRJ alters BP reactivity in 14 healthy estrogen-deficient normotensive postmenopausal women (57 ± 4 years, 8 ± 5 years since menopause). Participants consumed 2 × 70 mL/day (800 mg nitrate) of BRJ or nitrate-depleted BRJ (placebo) for 4 days, separated by a washout period (≥ 7 days). Continuous beat-to-beat mean arterial BP (MAP) and heart rate (HR) were measured at rest and during isometric handgrip exercise (IHG; 30% of maximal voluntary contraction), post-exercise ischemia (PEI) and cold pressor test (CPT). Data is presented as mean ± SD. We found no difference in the peak MAP response to IHG (Δ 16 ± 8 vs. 16 ± 6 mmHg, p = 0.60), PEI (Δ 11 ± 4 vs. 12 ± 7 mmHg, p = 0.32) or CPT (Δ 23 ± 11 vs 23 ± 10 mmHg, p = 0.93) between BRJ intake and placebo. Likewise, no difference was observed for SBP, DBP, or HR responses to either stressor (all: p>0.05). These findings suggest that short-term inorganic nitrate supplementation does not modify cardiovascular reactivity to IHG, PEI or CPT in healthy postmenopausal women.

Keywords:  Beetroot juice; Cold-pressor test; Exercise pressor reflex; Metaboreflex

DOI:  https://doi.org/10.1007/s00421-026-06430-3