bims-mistre 2025-07-13 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–07–13
fifteen papers selected by
Ellen Siobhan Mitchell, MitoQ

The role of ginseng in aging: Insights into regulatory T cells activation and mitochondrial regulation.
The Role of Estrogen in Mitochondrial Disease.
Aberrant Mitochondrial Metabolism in Alzheimer's Disease Links Energy Stress with Ferroptosis.
Mitochondrial dysfunction and aging: multidimensional mechanisms and therapeutic strategies.
Is NAD+ a key factor in ovarian aging and dysfunction? Insights and uncertainties from current research.
Mitochondrial Dysfunction and Defects in Mitochondrial Adaptation to Exercise Training in the Muscle of Patients With COPD: Disease Versus Disuse.
Oocyte and dietary supplements: a mini review.
Pro-longevity compounds extend Caenorhabditis elegans male lifespan and reproductive healthspan.
Integrative bioinformatics and machine learning approaches reveal oxidative stress and glucose metabolism related genes as therapeutic targets and drug candidates in Alzheimer's disease.
Hormonal modulation, mitochondria and Alzheimer's prevention: the role of GLP-1 agonists and estrogens.
Mitochondria-Targeted ROS-Scavenging Polymer Protects the Hepatocytes and Macrophages against Hepatic Ischemia-Reperfusion Injury.
Impacts of supplementation with pomegranate on cardiometabolic risk factors: A systematic review and dose-response meta-analysis.
ROS transfer at peroxisome-mitochondria contact regulates mitochondrial redox.
Non-pungent capsiate enhances longevity and healthspan in Caenorhabditis elegans via transient receptor potential (TRP) channels.
A noncanonical cGAS-STING pathway drives cellular and organismal aging.

J Ginseng Res. 2025 Jul;49(4): 376-388

The role of ginseng in aging: Insights into regulatory T cells activation and mitochondrial regulation.

Hamid Iqbal, Dong-Kwon Rhee.

  A hallmark of aging is the progressive decline in resilience to stress and mitochondrial activity. As mitochondrial function decreases with aging, mitochondrial DNA (mtDNA) is shed under apoptotic stress, resulting in a persistent low-level of sterile inflammation (called inflammaging) that induces the aging program. In response to inflammaging, the body activates a compensatory anti-inflammatory response, including the activation of regulatory T (Treg) cells, to prevent excessive tissue damage. Recent studies have highlighted the dysfunction of Treg cells in elderly patients, suggesting that their critical role in the mitigation of aging. Additionally, mitochondrial electron transport chain (ETC) complexes, particularly complexes II and III, are essential for the function of Th1 and Treg cells, respectively. Since centenarians experience less inflammaging, this review aims to explore the anti-aging properties of ginseng. Research has shown that ginseng and its active compounds, ginsenosides, increase Treg cells population in aged mice and convert pro-inflammatory M1 macrophages into anti-inflammatory M2 macrophages. Furthermore, ginseng enhances antioxidant protein expression, decreases reactive oxygen species (ROS) production, restores mitochondrial ATP and membrane potential, and exerts anti-aging effects. Ginseng has been shown to extend lifespan, promote beneficial gut bacteria, and slow cognitive decline through its influence on immune cell circulation. Future research, including clinical trials, is needed to clarify the regulatory effects of ginseng on Treg cells, mitochondrial complexes, and their associated metabolites, as well as the interconnected mechanisms between them.

Keywords:  Aging; Ginseng; Inflammaging; Mitochondria; Regulatory T cells

DOI:  https://doi.org/10.1016/j.jgr.2025.05.005
Cell Mol Neurobiol. 2025 Jul 11. 45(1): 68

The Role of Estrogen in Mitochondrial Disease.

Xi Huang, Cun-Hui Pan, Fei Yin, Jing Peng, Li Yang.

  This review aims to investigate the potential role of estrogen in various mitochondrial diseases, such as Leber's Hereditary Optic Neuropathy and Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes, focusing on its effects on aging, oxidative stress, mitochondrial biogenesis, and mitophagy. Mitochondrial diseases have become important in modern medical research due to their complex genetic background and diverse clinical manifestations. Studies in recent years have shown that estrogen plays an essential role in physiological regulation and may also affect the health status of cells by regulating mitochondrial function, which in turn affects the occurrence and development of diseases. However, there is still a lack of systematic review of estrogen's specific mechanisms and roles in these diseases. This review will synthesize the relevant literature to explore the association between estrogen and mitochondrial diseases and its possible therapeutic prospects, aiming to provide a theoretical basis and reference for future research.

Keywords:  Aging; Estrogen; Mitochondrial biogenesis; Mitochondrial disease; Mitophagy; Oxidative stress

DOI:  https://doi.org/10.1007/s10571-025-01592-8
Adv Sci (Weinh). 2025 Jul 08. e04175

Aberrant Mitochondrial Metabolism in Alzheimer's Disease Links Energy Stress with Ferroptosis.

Francesca Alves, Darius Lane, Adam Wahida, Md Jakaria, Pawel Kalinowski, Adam Southon, Abdel Ali Belaidi, Teresa Samperi-Esteve, Triet Phu Minh Nguyen, Peng Lei, Marcus Krueger, Stefan Mueller, Marcus Conrad, Puja Agarwal, Sue E Leurgans, Julie Schneider, Ashley I Bush, Scott Ayton.

  Alzheimer's disease (AD) is defined by β-amyloid plaques and tau-containing neurofibrillary tangles, but the ensuing cellular derangements that culminate in neurodegeneration remain elusive. Here, a mechanistic link between two AD pathophysiological hallmarks: energy insufficiency and oxidative stress is revealed. It is demonstrated that mitochondrial function and glutathione (GSH) flux are coupled, impacting neuronal ferroptosis susceptibility. Analysis of proteomic data from the inferior temporal cortex of 625 subjects along a continuum of clinical and pathological changes in AD, reveals a prominent depletion of mitochondrial proteins. Biogenetic insufficiency in AD is reflected by a concurrent loss of GSH, which requires 2 ATP for its synthesis, and genetic and pharmacologic ATP depletion models confirm that ATP is rate-limiting for GSH. Accordingly, an unbiased association analysis uncovers mitochondrial proteins in positive correlation with total GSH (t-GSH) in AD subjects. But mitochondria also consume GSH via the SLC25A39 transporter. It is found that mitochondrial inhibition either increases or decreases ferroptosis susceptibility in cellular models, depending on contextual factors that dictate whether mitochondria act as a net GSH producer or consumer, respectively. Mitochondria therefore control GSH flux, and loss of energy output is consequently demonstrated as a liability for ferroptosis in AD.

Keywords:  ATP; alzheimer's disease; bioenergetics; ferroptosis; glutathione; mitochondria; neurodegeneration

DOI:  https://doi.org/10.1002/advs.202504175
Biogerontology. 2025 Jul 09. 26(4): 142

Mitochondrial dysfunction and aging: multidimensional mechanisms and therapeutic strategies.

Pei Wei, Xiaoyan Zhang, Chi Yan, Siyu Sun, Zhigang Chen, Fei Lin.

  Aging is an inherent phenomenon that is highly important in the pathological development of numerous diseases. Aging is a multidimensional phenomenon characterized by the progressive impairment of various cellular structures and organelle functions. The basis of human organ senescence is cellular senescence. Currently, with the increase in human life expectancy and the increasing proportion of the elderly population, the economic burden of diseases related to aging is becoming increasingly heavy worldwide, and an in-depth study of the mechanism of cellular aging is urgently needed. Aging, a multifactor-driven biological process, is closely related to mitochondrial dysfunction, which is the core pathological basis of a variety of age-related diseases. This article systematically reviews the molecular pathways by which mitochondrial dysfunction drives aging through multidimensional mechanisms such as metabolic reprogramming, epigenetic regulation, telomere damage, autophagy imbalance, and the senescence-associated secretory phenotype. Metabolic reprogramming promotes tumor progression and exacerbates energy metabolism disorders through abnormal activation of the PI3K/Akt/mTOR signaling pathways. The sirtuin family (such as SIRT1 and SIRT3) maintains mitochondrial homeostasis by regulating PGC-1α, FOXO3 and other targets. Telomere shortening directly inhibits mitochondrial biosynthesis through the p53-PGC-1α axis, leading to oxidative stress accumulation and a decline in organ function. The dual roles of autophagy (removing damaged mitochondria or inducing apoptosis) suggests that its homeostasis is essential for delaying aging. The SASP mediates the inflammatory microenvironment through the cGAS‒STING pathway, which is not only a marker of aging but also a driving force of disease progression. Future studies need to integrate multiomics techniques to analyze the interaction network between mitochondria and other organelles, such as the endoplasmic reticulum and lysosomes, and explore precise intervention strategies targeting sirtuins, AMPK and telomerase. Combined therapies targeting metabolic reprogramming or SASP inhibition are expected to provide new ideas for delaying aging and preventing age-related diseases.

Keywords:  Aging; Autophagy; Epigenetic regulation; Metabolic reprogramming; Mitochondria; Telomere dysfunction

DOI:  https://doi.org/10.1007/s10522-025-10273-4
Biol Reprod. 2025 Jul 09. pii: ioaf140. [Epub ahead of print]

Is NAD+ a key factor in ovarian aging and dysfunction? Insights and uncertainties from current research.

Valeria Cordone, Teresa Vergara, Stefano Falone, Carla Tatone, Giovanna Di Emidio.

  Recent findings highlight NAD+ as a central regulator of various cellular processes, including energy metabolism, stress response, and aging. The growing evidence of the benefits associated with dietary NAD+ precursors has elevated NAD+ to a promising therapeutic target for addressing female infertility. This review aims to evaluate existing literature on the mechanisms governing the availability and utilization of NAD+ in the ovaries and its alterations in female reproductive disorders, with a particular focus on ovarian aging and dysfunction including polycystic ovary syndrome (PCOS) and premature ovarian insufficiency (POI). Alongside data from in vivo and in vitro studies on various NAD+ boosters, this review incorporates findings from research on genetic mutations, polymorphisms in human and animal populations, and insights from transgenic animal models. The present work emphasizes that NAD+ deficiency is largely driven by a combination of factors, including heightened consumption, impaired utilization efficiency, and diminished biosynthesis or transport. Analysing these aspects, we suggest that the ovary possesses its own unique NAD+ metabolism, but our understanding of the mechanisms governing it is still in its infancy. Key questions remain unanswered, such as how NAD+ and its precursors are transported into oocytes and ovarian cells, their specific preferences for different NAD+ precursors, as well as the specific changes associated with different ovarian dysfunctions. Finally, in this review methods for studying NAD+ metabolism are reported as essential tools to properly investigate the potential of NAD+ boosting therapies for counteracting ovarian aging and dysfunction.

Keywords:  Aging; Female fertility; Flim; Mitochondria; Nampt; Oocyte; Pcos; Sirtuins

DOI:  https://doi.org/10.1093/biolre/ioaf140
Acta Physiol (Oxf). 2025 Aug;241(8): e70079

Mitochondrial Dysfunction and Defects in Mitochondrial Adaptation to Exercise Training in the Muscle of Patients With COPD: Disease Versus Disuse.

Aldjia Abdellaoui, Farés Gouzi, Cécile Notarnicola, Annick Bourret, Amandine Suc, Dalila Laoudj-Chenivesse, Nelly Héraud, Jacques Mercier, Christian Préfaut, Maurice Hayot, Pascal Pomiès.

   AIM: Chronic obstructive pulmonary disease (COPD) is frequently associated with skeletal muscle dysfunction, having a considerable impact on exercise tolerance and patient prognosis. Mitochondria play a role in skeletal muscle weakness and exercise intolerance in COPD, but the majority of studies on mitochondrial function are biased by the fact that physical activity is greater in healthy subjects than in patients. Furthermore, exercise training (ET) has been proposed as a therapeutic strategy to prevent skeletal muscle dysfunction in COPD, but very few results are available on mitochondrial adaptation in response to ET.
METHODS: Skeletal muscle mitochondrial function and the potential efficacy of ET on this function were compared between 12 patients with COPD and 21 healthy subjects with similar low levels of physical activity. Various markers of mitochondrial respiration, oxidative stress, biogenesis, and dynamics were assessed.
RESULTS: Lower oxidative phosphorylation (OxPhos; p < 0.001) and increased nonphosphorylating respiration (p = 0.025) and mitochondrial oxidative damage (lipid peroxidation (p = 0.014) and protein carbonylation (p = 0.020)) were observed in patients. While ET increased OxPhos efficiency (p = 0.011) and reduced nonphosphorylating respiration (p < 0.001) and lipid peroxidation (p < 0.001) in patients' muscle mitochondria, it fails to improve maximal respiration (p = 0.835) and expression of the antioxidant enzyme MnSOD (p = 0.606), mitochondrial transcription factor TFAM (p = 0.246), and mitochondrial complexes I, III, and IV (p = 0.816, p = 0.664, p = 0.888, respectively) as observed in healthy subjects.
CONCLUSION: The mitochondrial dysfunction and the defects in mitochondrial adaptation to ET that we observe in the muscle of patients with COPD are intrinsic to the disease and do not arise from muscle disuse.

Keywords:  COPD; exercise; mitochondrial dysfunction; muscle; oxidative stress; pulmonary rehabilitation

DOI:  https://doi.org/10.1111/apha.70079
Front Cell Dev Biol. 2025 ;13 1619758

Oocyte and dietary supplements: a mini review.

Hao Chen, Shuoqi Wang, Meiying Song, Dongxia Yang, Hongmei Li.

  Rising rates of infertility have stimulated interest in dietary supplements to improve oocyte quality through mitochondrial function, antioxidant activity, and epigenetically regulated metabolic pathways. Mitochondria provides adenosine triphosphate for oocyte maturation, with Coenzyme Q10 (CoQ10) demonstrating efficacy in animal models by alleviating oxidative damage and enhancing blastocyst formation. In aged mice, CoQ10 restored mitochondrial activity and reduced chromosomal abnormalities, while preliminary human studies noted improved embryo quality in poor responders, though randomized controlled trials (RCTs) remain inconclusive. Antioxidants like melatonin counter reactive oxygen species (ROS)-induced spindle defects and mitochondrial dysfunction, showing benefits in murine oocyte maturation and blastocyst development. Resveratrol enhanced bovine oocyte quality through metabolic modulation. Human trials on antioxidants show reduced granulosa cell stress but lack robust evidence. Epigenetically, folate supports DNA methylation critical for embryonic gene expression, with deficiencies linked to hyperhomocysteinemia and developmental defects in animal models. Human observational studies associate folate-rich diets with lower aneuploidy and better assisted reproductive technology outcomes, while omega-3 fatty acids aid chromatin remodeling via histone deacetylase regulation. Despite compelling preclinical data, human trials face inconsistencies due to variable designs and confounders. Standardized RCTs are urgently needed to translate mechanistic insights into clinical guidelines, addressing the disconnect between animal studies and human reproductive outcomes.

Keywords:  clinical trials; dietary supplements; lifestyle changes; oocyte process; quality ovary

DOI:  https://doi.org/10.3389/fcell.2025.1619758
bioRxiv. 2025 Jul 02. pii: 2025.06.29.662228. [Epub ahead of print]

Pro-longevity compounds extend Caenorhabditis elegans male lifespan and reproductive healthspan.

Rose S Al-Saadi, Patrick C Phillips.

Sex differences in aging are robust and ubiquitous. Demographic differences in aging generated by sex have long been recognized, but the underlying biological basis for these differences and the potential for sex-specific interventions remain understudied. To explore sex differences in the response to pro-longevity interventions, we utilized the C. elegans aging model and asked whether male lifespan and reproductive healthspan can be extended via compounds known to have pro-longevity effects in hermaphrodites. We tested seven different compounds at two concentrations each and found that lifespan was extended under all tested conditions. However, reproductive healthspan measured by mating success in late life improved under only two tested conditions, sulforaphane and metformin. These results demonstrate that lifespan and healthspan can be decoupled in C. elegans males and offer a new framework for screening pro-longevity compounds and for studying sex differences in aging in a classical aging model.

DOI: https://doi.org/10.1101/2025.06.29.662228
Front Immunol. 2025 ;16 1572468

Integrative bioinformatics and machine learning approaches reveal oxidative stress and glucose metabolism related genes as therapeutic targets and drug candidates in Alzheimer's disease.

Fatima Noor, Sidra Aslam, Ignazio S Piras, Cecilia Tremblay, Thomas G Beach, Geidy E Serrano.

   Background: Alzheimer's disease (AD), the most common form of dementia, has treatments that slow but do not stop cognitive decline. Additional treatments are based on its pathogenic mechanisms are needed. Evidence has long highlighted oxidative stress and impaired glucose metabolism as crucial factors in AD pathogenesis. Therefore, in this study we aimed to find key AD pathogenic pathways combining genes involved in oxidative stress and glucose metabolism as well as potential small-molecule therapeutic agents.
Methods: Using autopsy brain RNA sequencing data (GSE125583) derived from the Arizona Study of Aging and Brain and Body Donation Program, AD-related genes were identified via differential gene expression, pathway and coexpression analysis. Oxidative stress and glucose metabolism genes were correlated to pinpoint module genes. GSE173955 was used an independent dataset was used for validation, conducting molecular docking, assessing hub genes for AD, and integrating machine learning approaches.
Results: We identified 13,982 differentially expressed genes (DEGs) in AD patients. Through WGCNA coexpression analysis, 1,068 genes were linked to AD-specific modules. Pearson's correlation analysis highlighted 99 genes involved in oxidative stress and glucose metabolism. Overlap analysis of DEGs, module genes, and these metabolic genes revealed 21 key overlapping targets. PPI network and receiving operating curve (ROC) curve analyses then identified AKT1 and PPARGC1A as diagnostic hub genes for AD. Machine learning-based virtual screening of small molecules identified various inhibitors and enhancers with drug-like potential targeting AKT1 (upregulated) and PPARGC1A (downregulated), respectively. Among others, the Random Forest model was the most reliable for predicting molecular activity. Molecular docking further validated the binding affinities of these small molecules (inhibitors/enhancers) to AKT1 and PPARGC1A.
Conclusion: This study identified AKT1 and PPARGC1A as potential therapeutic targets in AD. We discovered drug candidates with strong binding affinities, offering new avenues for effective AD treatment strategies.

Keywords:  Alzheimer’s disease; bioinformatics; glucose metabolism; machine learning; oxidative stress

DOI:  https://doi.org/10.3389/fimmu.2025.1572468
Front Mol Biosci. 2025 ;12 1622186

Hormonal modulation, mitochondria and Alzheimer's prevention: the role of GLP-1 agonists and estrogens.

Fernando Lizcano, Daniela Sanabria, Eliana Aviles.

  Alzheimer's disease (AD) is the most prevalent cause of dementia worldwide, disproportionately affecting women and lacking effective disease-modifying therapies. While traditional approaches have focused on amyloid β (Aβ) plaques and tau pathology, emerging evidence highlights the role of metabolic dysfunction, mitochondrial impairment, and hormonal signaling in the pathogenesis of AD. Estrogens exert neuroprotective effects by modulating synaptic plasticity, enhancing mitochondrial bioenergetics, and reducing oxidative stress and inflammation. Similarly, glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for the treatment of type 2 diabetes, have demonstrated promising cognitive benefits, potentially mediated through improved insulin signaling, neuronal survival, and reduced β-amyloid (Aβ) and tau burden. This review explores the converging mechanisms through which estrogens and GLP-1RAs may act synergistically to prevent or delay the onset of AD. We examine the influence of sex differences in mitochondrial dynamics, estrogen receptor distribution, and GLP-1 signaling pathways, particularly within central nervous system regions implicated in AD. Preclinical studies using GLP-1-estrogen conjugates have shown enhanced metabolic and neuroprotective outcomes, accompanied by reduced systemic hormonal exposure, suggesting a viable therapeutic strategy. As the global prevalence of AD continues to rise, especially among postmenopausal women, dual agonism targeting estrogen and GLP-1 receptors may represent a novel, physiologically informed approach to prevention and intervention. Ongoing clinical trials and future research must consider sex-specific factors, receptor polymorphisms, and brain-region selectivity to optimize the translational potential of this combined strategy.

Keywords:  Alzheimerr′s disease; GLP-1 agonists; estrogens; metabolism; prevention

DOI:  https://doi.org/10.3389/fmolb.2025.1622186
Acta Biomater. 2025 Jul 03. pii: S1742-7061(25)00481-7. [Epub ahead of print]

Mitochondria-Targeted ROS-Scavenging Polymer Protects the Hepatocytes and Macrophages against Hepatic Ischemia-Reperfusion Injury.

Haitao Hu, Yanpeng Liu, Chang Xu, Jun Chen, Shengjun Xu, Yixiao Tang, Yuhao Ren, Zhengxing Lian, Rui Wang, Siyu Chen, Yiyang Sun.

  While liver transplantation (LT) is the most effective therapeutic intervention for end-stage liver diseases, hepatic ischemia-reperfusion injury (HIRI) remains a major determinant of adverse clinical outcomes. Mitochondrial reactive oxygen species (ROS) have been implicated in HIRI pathogenesis. In this study, we conjugated the small molecule, antioxidant 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) with a neutral, long-circulating, and mitochondria-targeting polymer, poly[2-(N-oxide-N,N-diethylamino)ethyl methacrylate] (OPDEA), to obtain a conjugate containing 10% TEMPO (OPT10). OPT10 exhibited reliable biocompatibility and efficiently mitigated mitochondrial ROS in hepatocytes; it was also readily internalized into hepatic macrophages, promoting polarization to the anti-inflammatory M2 phenotype for over 24 h. Through these effects, together with reducing oxidative stress and decreasing activation of the MAPK pathway, OPT10 could attenuate innate immune-driven inflammation and alleviate HIRI. Compared with clinically used antioxidants such as N-acetylcysteine (NAC) and glutathione (GSH), OPT10 exhibited superior efficacy in ameliorating HIRI in a mouse model and can be considered a promising candidate for clinical translation. STATEMENT OF SIGNIFICANCE: Liver transplantation remains an effective therapeutic intervention for end-stage liver diseases. Alleviating hepatic ischemia-reperfusion injury (HIRI) is crucial for enhancing graft viability and improving long-term patient outcomes. Excessive production of mitochondrial reactive oxygen species (mtROS) during HIRI not only exacerbates hepatocellular damage but also promotes macrophage M1 polarization, thereby driving hepatic inflammation and injury. In this study, we synthesized a mitochondria-targeted ROS-scavenging polymer that enabled precise delivery to both hepatocytes and macrophages, effectively alleviating liver injury and offering novel insights into therapeutic strategies for HIRI.

Keywords:  ROS-scavenging; hepatic ischemia-reperfusion injury; macrophage; mitochondria-targeted; therapeutic polymer

DOI:  https://doi.org/10.1016/j.actbio.2025.07.004
Nutr Metab Cardiovasc Dis. 2025 May 28. pii: S0939-4753(25)00308-4. [Epub ahead of print] 104154

Impacts of supplementation with pomegranate on cardiometabolic risk factors: A systematic review and dose-response meta-analysis.

Shooka Mohammadi, Javad Heshmati, Nima Baziar, Somayeh Ziaei, Farnaz Farsi, Sara Ebrahimi, Tofigh Mobaderi, Tanin Mohammadi, Hassan Mir.

   AIMS: It has been suggested that supplementation with pomegranate (PO) may improve the risk factors related with cardiometabolic syndrome (CMS). This systematic review and dose-response meta-analysis of randomized controlled trials (RCTs) was conducted to assess the impacts of PO supplementation on cardiovascular risk factors and CMS.
DATA SYNTHESIS: A comprehensive search of major databases including PubMed, Scopus, and Web of Science was implemented to identify appropriate RCTs that were published until January 2024. A random-effects model was applied for the meta-analysis and I2 was used to report the heterogeneity between included studies. After the screening of the search results a 53 RCTs with 2306 participants included in this meta-analysis. The findings revealed that PO supplementation substantially reduced body weight (standardized mean difference (SMD): -0.14 kg, 95 % CI: -0.25, -0.03; P = 0.01), diastolic blood pressure (DBP) (SMD: -0.39 mmHg, 95 % CI: -0.59, -0.18; P < 0.001), body mass index (BMI) (SMD: -0.17 kg/m2, 95 % CI: -0.30, -0.04; P = 0.01), systolic blood pressure (SBP) (SMD: -0.49 mmHg, 95 % CI: -0.68, -0.31; P < 0.001), serum fasting blood glucose (FBG) (SMD: -0.15 mg/dL, 95 % CI: -0.26, -0.04; P = 0.01), and total cholesterol (TC) (SMD: -0.12 mg/dL, 95 % CI: -0.24, -0.00; P = 0.04) while elevating high-density lipoprotein (HDL) levels (SMD: 0.27 mg/dL, 95 % CI: 0.08, 0.47; P < 0.001) compared to control groups. No substantial changes were observed in waist-to-hip ratio (WHR), homeostatic model assessment of insulin resistance (HOMA-IR), waist circumference (WC), serum values of hemoglobin A1c (HbA1c), alanine transaminase (ALT), triglycerides (TG), low-density lipoprotein (LDL), insulin, and aspartate transferase (AST) levels between PO and placebo groups.
CONCLUSION: PO consumption may improve specific risk factors associated with CMS. Further RCTs with extended durations and larger sample sizes are suggested to corroborate these findings.
PROSPERO REGISTRATION NUMBER: CRD42024557368.

Keywords:  Cardiometabolic syndrome; Cardiovascular prevention; Nutritional supplementation; Pomegranate; Risk factor management

DOI:  https://doi.org/10.1016/j.numecd.2025.104154
Science. 2025 Jul 10. 389(6756): 157-162

ROS transfer at peroxisome-mitochondria contact regulates mitochondrial redox.

Laura F DiGiovanni, Prabhsimran K Khroud, Ruth E Carmichael, Tina A Schrader, Shivneet K Gill, Kyla Germain, Robert Y Jomphe, Christoph Wiesinger, Maxime Boutry, Maki Kamoshita, Daniel Snider, Garret Stubbings, Rong Hua, Noel Garber, Christian Hacker, Andrew D Rutenberg, Roman A Melnyk, Johannes Berger, Michael Schrader, Brian Raught, Peter K Kim.

Maintenance of mitochondrial redox homeostasis is of fundamental importance to cellular health. Mitochondria harbor a host of intrinsic antioxidant defenses, but the contribution of extrinsic, nonmitochondrial antioxidant mechanisms is less well understood. We found a direct role for peroxisomes in maintaining mitochondrial redox homeostasis through contact-mediated reactive oxygen species (ROS) transfer. We found that ACBD5 and PTPIP51 form a contact between peroxisomes and mitochondria. The percentage of these contacts increased during mitochondrial oxidative stress and helped to maintain mitochondrial health through the transfer of mitochondrial ROS to the peroxisome lumen. Our findings reveal a multiorganelle layer of mitochondrial antioxidant defense-suggesting a direct mechanism by which peroxisomes contribute to mitochondrial health-and broaden the scope of known membrane contact site functions.

DOI: https://doi.org/10.1126/science.adn2804
Food Funct. 2025 Jul 11.

Non-pungent capsiate enhances longevity and healthspan in Caenorhabditis elegans via transient receptor potential (TRP) channels.

Nathan Lyttle, Mohankumar Amirthalingam, Julia Bali, Alan Yazid Chavez Hita Wong, Juan Gerardo Flores Iga, Shinkichi Tawata, Padma Nimmakayala, Umesh K Reddy.

Capsiate, a non-pungent capsaicin analog found mainly in low-pungency cultivars of Capsicum annuum L., exhibits diverse pharmacological and health-promoting properties. However, despite its equipotency, it remains less extensively studied than capsaicin. Here, we systematically investigated the toxicity profile and the life- and health-promoting mechanisms of capsiate using the genetically tractable model organism Caenorhabditis elegans (C. elegans). Capsiate was found to be safe and exerted a concentration-dependent biphasic effect, with an optimal dose (10 μmol L-1) enhancing stress resilience, reducing intracellular reactive oxygen species (ROS) levels, and extending lifespan. Mechanistically, capsiate-mediated effects required the transient receptor potential (TRP) channels TRPA-1 (TRPA1) and OSM-9 (TRPV). Activation of TRPA-1 initiated calcium-sensitive PKC-2 signaling via SGK-1, which subsequently activated DAF-16/FoxO to transactivate key longevity-related targets, including hsp-16.2 and sod-3. In parallel, TRPA-1 activation also recruited the CaMKII-p38 MAPK pathway, leading to SKN-1/Nrf2 nuclear localization and upregulation of gerontogenes, gcs-1, gst-4, and gst-10. Beyond these molecular effects, capsiate attenuated age-associated declines in learning ability, motor function, and stress resilience, highlighting its potential to promote health during aging. Together, these findings provide the first mechanistic insights into capsiate-mediated healthy lifespan extension and stress resilience in C. elegans, offering a promising foundation for future therapeutic strategies targeting age-related diseases.

DOI: https://doi.org/10.1039/d5fo01607j
Proc Natl Acad Sci U S A. 2025 Jul 15. 122(28): e2424666122

A noncanonical cGAS-STING pathway drives cellular and organismal aging.

Rafael Cancado de Faria, Lilian N D Silva, Barbara Teodoro-Castro, Kyle S McCommis, Elena V Shashkova, Susana Gonzalo.

  Accumulation of cytosolic DNA has emerged as a hallmark of aging, inducing sterile inflammation. Stimulator of interferon genes (STING) protein translates the sensing of cytosolic DNA by cyclic-GMP-AMP synthase (cGAS) into an inflammatory response. However, the molecular mechanisms whereby cytosolic DNA-induced cGAS-STING pathway leads to aging remain poorly understood. We show that STING does not follow the canonical pathway of activation in human fibroblasts passaged (aging) in culture, senescent fibroblasts, or progeria fibroblasts (from Hutchinson-Gilford progeria syndrome patients). Despite cytosolic DNA buildup, features of the canonical cGAS-STING pathway like increased cGAMP production, STING phosphorylation, and STING trafficking to perinuclear compartment are not observed in progeria/senescent/aging fibroblasts. Instead, STING localizes at endoplasmic reticulum, nuclear envelope, and chromatin. Despite the nonconventional STING behavior, aging/senescent/progeria cells activate inflammatory programs such as the senescence-associated secretory phenotype and the interferon response, in a cGAS and STING-dependent manner, revealing a noncanonical pathway in aging. Importantly, progeria/aging/senescent cells are hindered in their ability to activate the canonical cGAS-STING pathway with synthetic DNA, compared to young cells. This deficiency is rescued by activating vitamin D receptor signaling, unveiling mechanisms regulating the cGAS-STING pathway in aging. Significantly, in HGPS, inhibition of the noncanonical cGAS-STING pathway ameliorates cellular hallmarks of aging, reduces tissue degeneration, and extends the lifespan of progeria mice. Our study reveals that a new feature of aging is the progressively reduced ability to activate the canonical cGAS-STING pathway in response to cytosolic DNA, triggering instead a noncanonical pathway that drives senescence/aging phenotypes.

Keywords:  aging; cGAS; cytosolic DNA; senescence-associated secretory phenotype; stimulator of interferon genes

DOI:  https://doi.org/10.1073/pnas.2424666122