bims-mistre 2026-07-12 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–07–12
25 papers selected by
Ellen Siobhan Mitchell, MitoQ

Advances in the Core Role and Mechanisms of Mitochondrial Dysfunction in Alzheimer's Disease.
Plant-derived mitochondria mitigate aging-related neurodegeneration by reprogramming microglial mitochondrial energy metabolism.
Dysfunctional Mitochondria in Microglia Drive Cognitive Aging and Neurodegeneration via cGAS-STING.
Endosymbiotic theory of aging revisited: Age-related leakage of mitochondrial dsDNA/RNA stimulates cytosolic nucleic acid sensors which remodel the immune network and promote the aging process.
Saliva cell-free mitochondrial DNA (cf-mtDNA) as a dynamic biomarker of stress and emotion in daily life: Evidence from two independent repeated-measures studies.
L-citrulline as a nitric oxide-modulating therapeutic adjunct to exercise: effects on vascular function, arterial stiffness, and cardiometabolic health in postmenopausal and older women.
Inhibition of peroxisomal protein PRX-11 promotes longevity in Caenorhabditis elegans via enhancements to mitochondria.
Mitoquinone Prevents Cardiac Dysfunction by Normalizing Mitochondrial ROS and Calcium Handling in Acute Myocardial Infarction.
Cardiovascular Benefits of Menopause Hormone Treatment is Age-Dependent.
SUMOylation in Mitochondrial Quality Control: Mechanisms and Implications for Neurodegenerative Disease.
Regulation of NLRP3 inflammasome signaling in Alzheimer's disease: emerging neuroprotective role of phytochemicals.
Eight Weeks of MitoQ Supplementation Does Not Alter Kidney Function or Urinary Kidney Injury Biomarkers in Middle-Aged and Older Adults.
N-Acetylaspartate Synthesis as a Thermodynamic Relief Mechanism for Mitochondrial Aspartate Aminotransferase.
Dopamine-driven mitochondrial reverse electron transport in immune cells mediates gut-brain ROS signaling during sleep deprivation.
A cold-induced GDF15-secreting adipocyte subpopulation regulates energy homeostasis through endocrine signaling.
Nicotinamide mononucleotide ameliorates high glucose/high fat-induced cardiomyocyte metabolic dysfunction through SIRT1-mediated CPT1A stabilization.
Mitochondrial-ER stress crosstalk in osteoarthritis: From ageing-associated chondrocyte dysfunction to emerging therapeutics.
Emodin alleviates radiation-induced pulmonary fibrosis by targeting cellular senescence via the mtDNA-cGAS-STING axis.
Brain health across the lifespan and the impact of nutrition, exercise, microbiota, and sleep.
Effects of hesperidin supplementation on inflammation and oxidative stress in overweight or obese individuals: a systematic review and meta-analysis of randomized controlled trials.
C-reactive protein-triglyceride-glucose index and risk of incident depressive symptoms in older adults: an eight-year follow-up study from ELSA.
Association of age at menopause with cardiovascular disease and mortality:insights from NHANES and a clinical cohort.
A multi-modal longevity protocol integrating lifestyle, supplements, and autologous pro-regenerative cell-conditioned media: a pilot study.
Cognitive and affective effects of L-Theanine: a systematic review and meta-analysis of 31 randomized trials.
The special extract ERr 731® from the root of rhapontic rhubarb (Rheum rhaponticum): efficacy in headache/migraine and further climacteric complaints in women in the perimenopause.

Brain Behav. 2026 Jul;16(7): e71418

Advances in the Core Role and Mechanisms of Mitochondrial Dysfunction in Alzheimer's Disease.

Tianyi Gu, Hangyan Guo, Zixin Guo, Shengyu Hua.

   INTRODUCTION: Alzheimer's disease (AD) is a complex neurodegenerative disorder whose pathogenesis involves multi-level pathological alterations. This review aims to systematically elucidate the central role and multifaceted molecular mechanisms of mitochondrial dysfunction in the progression of AD.
METHODS: A comprehensive analysis of the existing literature was conducted, synthesizing findings from studies investigating mitochondrial involvement in AD pathology. The review focused on key mechanistic pathways, including energy metabolism deficits, oxidative stress, synaptic damage, mitochondrial dynamics, mitochondria-associated membranes (MAMs), mitophagy, and the gut-brain axis.
RESULTS: The analysis revealed several critical mechanisms linking mitochondrial dysfunction to AD progression: (i) impaired mitochondrial energy metabolism, which establishes a causal relationship with oxidative stress and synaptic injury; (ii) dysregulation of mitochondrial fusion/fission dynamics, particularly the aberrant interactions of amyloid-beta (Aβ) and p-Tau with the fission protein Drp1 and the channel protein VDAC1; (iii) dysfunction of mitochondria-associated membranes (MAMs); (iv) defective mitophagy involving both the PINK1/Parkin pathway and receptor-mediated pathways; and (v) bidirectional crosstalk between mitochondria and the gut-brain axis. These interconnected pathways converge to amplify neuroinflammation and neuronal death.
CONCLUSION: Accumulated evidence positions mitochondrial dysfunction as a critical hub that integrates Aβ/Tau pathology, neuroinflammation, and neuronal loss, thereby perpetuating a self-sustaining vicious cycle in AD. Targeting mitochondrial bioenergetics, dynamics, quality control, and the mitochondria-inflammation axis offers substantial therapeutic promise. Emerging small molecules such as SS31 and DDQ have demonstrated protective effects in preclinical models. Future investigations should prioritize mechanistic dissection and translational research to facilitate the clinical development of mitochondria-targeted therapies for AD.

Keywords:  Alzheimer's disease; inflammation; mitochondrial dysfunction; mitophagy; neurodegeneration

DOI:  https://doi.org/10.1002/brb3.71418
Transl Neurodegener. 2026 Jul 08. pii: 30. [Epub ahead of print]15(1):

Plant-derived mitochondria mitigate aging-related neurodegeneration by reprogramming microglial mitochondrial energy metabolism.

Yun Teng, Chao Luo, Qingbo Xu, Jingyao Mu, Lucy Teng, Hongjia Qian, Yinan Huang, Minmin Liu, Lifeng Zhang, Juw Won Park, Jae Yeon Hwang, Maiying Kong, Jun Yan, Michael L Merchant, Huang-Ge Zhang.

   BACKGROUND: Intercellular mitochondrial transfer is pivotal in both healthy and pathological states. Supplementing healthy mitochondria is emerging as a promising therapeutic approach for various diseases. Non-immunogenic edible plants, which contain mitochondria, offer a novel avenue for such therapies.
METHODS: Mitochondria were isolated from several commonly consumed edible plants (P-Mit) using differential centrifugation followed by sucrose gradient ultracentrifugation. The distribution of P-Mit, particularly in the brain, was examined with a mitochondrial membrane-potential dye and an imaging system. As a proof of concept, the molecular interactions underlying turmeric-derived mitochondria (T-Mit) uptake by microglia were elucidated through affinity precipitation coupled with mass spectrometry. By labeling with gold-nanoparticles in a distinct triangular or spherical shape followed by electron microscopy and energy dispersive spectroscopy analysis, we demonstrated the physical fusion of T-Mit and animal mitochondria in microglia. Mitochondrial functions such as superoxide levels, ATP-linked mitochondrial respiration, glycolysis and electron transport chain activity were assessed to determine the impact of T-Mit on aging-related microglial dysfunction. Next-generation small RNA sequencing revealed the underlying mechanism by which T-Mit-derived small RNAs modulate the expression of NADH dehydrogenase (ND) genes in microglia.
RESULTS: Orally administered T-Mit travelled from the gut to the brain in aged male mice, where they fused with microglial mitochondria (M-Mit), reprogramming M-Mit energy metabolism and reversing aging-related cognitive dysfunction. Specifically, T-Mit was taken up by microglia via the phagocytic receptor TREM2. Subsequently, T-Mit fused with M-Mit in a mitofusin 1-dependent manner. The T-Mit microRNAs Tae-miR319 and Osa-miR166a-3p then integrated into M-Mit, inhibiting the expression of complex I subunits ND4 and ND5. This inhibition alleviated reverse electron transport (RET) at complex I, reducing reactive oxygen species (ROS) production and facilitating ATP production, ultimately rescuing aging-related cognitive decline. Data from elderly human subjects also showed overactivation of the RET process and overproduction of ROS, accompanied by low ATP levels in microglia.
CONCLUSIONS: Our findings fundamentally alter our understanding of the regulation of mammalian mitochondrial biology by P-Mit and may lead to P-Mit-based transfer therapy for preventing or treating human mitochondrial disorder-related diseases.

Keywords:  Aging-related neurodegeneration; Cardiolipin; Cross-kingdom mitochondrial fusion; Microglia mitochondrial metabolism; Mitochondria transfer therapy; NADH dehydrogenase (Complex I); Plant mitochondrial microRNAs; Plant mitochondria; Reactive oxygen species (ROS); Reverse electron transport (RET)

DOI:  https://doi.org/10.1186/s40035-026-00565-1
Neurosci Bull. 2026 Jul 07.

Dysfunctional Mitochondria in Microglia Drive Cognitive Aging and Neurodegeneration via cGAS-STING.

Guanqin Ma, Erlin Wang, Xiaoxu Yan, Xiang-Xiong Xu, Xiaohong Li, Xueling Ma, Wan-Hua Yang, Jianxiong Zeng, Xiaochun Xie.

  Mitochondrial dysfunction induces metabolic dysregulation in immune cells that is etiologically associated with age-related brain disorders. However, how dysfunctional mitochondria in microglia-the brain-resident immune cells-initially affect neurological function remains incompletely understood. Here, we demonstrate that dysfunctional mitochondria in microglia, induced by the conditional knockout of mitochondrial transcription factor A, act as triggers of metabolic dysregulation, cognitive aging, and neurodegeneration in adult mice. Notably, this metabolic disturbance induces a microglial transition to states associated with neuroinflammatory activation and neurodegenerative disease, thereby triggering multiple layers of pathological cascade reactions among other brain cell types and shaping a neuroinflammaging state at single-cell resolution. Mechanistically, mitochondrial dysfunction activates the innate immune cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which mediates immune sensing of cytosolic DNA in microglia and contributes to inflammaging. We further present evidence that combined treatment aimed at restoring metabolic homeostasis and inhibiting neuroinflammatory cGAS-STING partially rescues age-related neurological dysfunction in mice. Collectively, our findings reveal a link between mitochondrial dysfunction in microglia and cognitive aging, underscoring the significance of tightly regulated metabolism in age-associated neurological diseases.

Keywords:  Microglia; Mitochondrial dysregulation; Neurodegeneration; Neuroinflammaging; cGAS–STING

DOI:  https://doi.org/10.1007/s12264-026-01657-8
Biogerontology. 2026 Jul 07. pii: 124. [Epub ahead of print]27(4):

Endosymbiotic theory of aging revisited: Age-related leakage of mitochondrial dsDNA/RNA stimulates cytosolic nucleic acid sensors which remodel the immune network and promote the aging process.

Antero Salminen, Kai Kaarniranta, Anu Kauppinen.

  About 1.5-2 billion years ago, an endosymbiosis between aerobic α-proteobacteria and anaerobic archaeal cells generated mitochondria, i.e., organelles capable of producing oxidative energy. The bacterial genome was fundamentally reduced and a circular mitochondrial genome evolved containing mainly the genes coding for the subunits of the electron transport chain. Before the symbiotic event, there existed a virus-host co-evolution which involved the development of sensors for detecting dangerous viral DNA/RNA molecules. Endosymbiosis supplied eukaryotic cells not only with an oxidative powerhouse to allow the evolution of more complex multicellular organisms but it also meant that cells now housed an organelle which was able to generate reactive oxygen species (ROS) and to leak mitochondrial DNA (mtDNA) and double-stranded RNA (dsRNA) into the cytoplasm. There is now abundant evidence that during aging and age-related diseases mitochondria are prone to release both mtDNA and dsRNA. In the cytoplasm, mtDNA/dsRNA molecules activate a number of cytosolic nucleic acid sensors leading to the secretion of type-1 interferons (IFN) and many other cytokines which promote an age-related proinflammatory state. Currently, it is known that mtDNA can activate the cGAS-STING pathway, AIM2 inflammasomes, IFI16 receptors, and ZBP1 sensors and in addition mitochondrial dsRNA stimulates RIG-1/MDA5 signaling. Interestingly, there is abundant evidence that all these receptors are drivers of cellular senescence and inflammaging. For decades, there has been mounting evidence that mitochondria have a crucial role in the aging process. We will examine this question from the perspective of evolution and propose that mitochondrial evolution created an endogenic source for the leakage of dangerous mtDNA/dsRNA which subsequently stimulated cytosolic DNA/RNA sensors, an evolutionarily conserved viral defence mechanism. It seems that these two evolutionary events provided not only the basis for the inevitable process of aging but also ensuring the death of parental organisms.

Keywords:  Ageing; Bacterial origin; CGAS-STING; DNA/RNA sensors; Endosymbiosis; Evolution

DOI:  https://doi.org/10.1007/s10522-026-10470-9
Psychoneuroendocrinology. 2026 Jul 02. pii: S0306-4530(26)00212-X. [Epub ahead of print]192 107952

Saliva cell-free mitochondrial DNA (cf-mtDNA) as a dynamic biomarker of stress and emotion in daily life: Evidence from two independent repeated-measures studies.

Lauren Petri, Sun Ah Lee, David Shire, Samantha Leonard, Alexander Behnke, Idan Shalev, Jody Greaney, Lacy Alexander, David M Almeida, Martin Picard, Caroline Trumpff.

  The present study analyzes the impact of naturalistic stress and emotions on saliva cell-free mitochondrial DNA (cf-mtDNA) in daily life across two independent cohorts with different temporal resolutions. Study 1 examined the interaction between daily stress and major depressive disorder (MDD) on cf-mtDNA in young adults (n = 18, 8 MDD, 10 controls). Across four days, participants provided 4 saliva samples and nightly stress inventories. Among individuals with MDD, cf-mtDNA concentrations were 68% lower on days with reported stress exposure compared with days without reported stress exposure. Among stress-exposure days, a greater number and higher severity of stressors were associated with 24-27% lower cf-mtDNA concentrations. Study 2 extended this framework by implementing a finer temporal resolution in healthy young adults (n = 25), measuring saliva and momentary affective states with hourly ecological momentary assessments, up to 20 times per day for 2 days. Higher positive affect was associated with higher cf-mtDNA; however, this relationship weakened as negative affect increased. Exploratory analyses of individual emotions showed that cf-mtDNA tended to be higher during positive emotional states and lower during negative emotional states; however, person-specific models indicated that these associations, particularly for happiness and stress, varied substantially across participants. Overall, cf-mtDNA did not exhibit a uniform stress response in daily life; rather, the dynamics were dependent on diagnostic status and stress exposure timing in Study 1, and on momentary emotional context in Study 2. Accordingly, cf-mtDNA should be conceptualized as a dynamic biobehavioral signal rather than a static indicator of between-person differences.

Keywords:  Affect dynamics; Cell-free mitochondrial DNA (cf-mtDNA); Daily stress; Ecological momentary assessment (EMA); Major depressive disorder (MDD); Saliva biomarkers

DOI:  https://doi.org/10.1016/j.psyneuen.2026.107952
Amino Acids. 2026 Jul 09.

L-citrulline as a nitric oxide-modulating therapeutic adjunct to exercise: effects on vascular function, arterial stiffness, and cardiometabolic health in postmenopausal and older women.

Zhigang Chen.

  Postmenopausal women face increased risks of vascular dysfunction, loss of lean muscle mass, and reduced physical performance due to age-related hormonal and metabolic changes. These factors contribute to heightened cardiovascular risk and physical frailty. L-citrulline, a non-essential amino acid and precursor to nitric oxide (NO), has emerged as a potential therapeutic agent for improving vascular and muscular health. When combined with structured exercise, L-citrulline may enhance NO bioavailability, improve endothelial function, increase muscle perfusion, and potentiate exercise-induced adaptations. This review synthesizes current evidence on the combined impact of L-citrulline supplementation and exercise on endothelial function, arterial stiffness, leg muscle function, lean mass, and strength in postmenopausal women. Findings from preclinical and clinical studies suggest that this combined intervention can reduce arterial stiffness, enhance leg muscle strength, increase lean body mass, and improve overall physical function, potentially via NO-mediated vasodilation, the mechanistic target of rapamycin signaling, improved mitochondrial function, and reduced oxidative stress. These effects are especially relevant in postmenopausal populations at risk for cardiovascular disease and sarcopenia. While early results are promising, further high-quality randomized controlled trials are needed to confirm these benefits, establish optimal dosing strategies, and determine long-term clinical relevance.

Keywords:  Arterial stiffness; Endothelial function; Exercise; L-citrulline; Postmenopausal women

DOI:  https://doi.org/10.1007/s00726-026-03541-1
Aging (Albany NY). 2026 Jul 06. 18(1): 787-812

Inhibition of peroxisomal protein PRX-11 promotes longevity in Caenorhabditis elegans via enhancements to mitochondria.

Yash Flora, Dhriti Shastri, Kathryn R DeLeo, K Adam Bohnert.

  Peroxisomes execute essential functions in cells, including detoxification and lipid oxidation. Despite their centrality to cell biology, the relevance of peroxisomes to aging remains understudied. We recently reported that peroxisomes are degraded en masse via pexophagy during early aging in the nematode Caenorhabditis elegans, and we found that downregulating the peroxisome-fission protein PRX-11/PEX11 prevents this age-dependent pexophagy and extends lifespan. Here, we further investigated how prx-11 inhibition promotes longevity. Remarkably, we found that reducing peroxisome degradation with age led to concurrent improvements in another organelle: the mitochondrion. Animals lacking prx-11 function showed tubular, youthful mitochondria in older ages, and these enhancements required multiple factors involved in mitochondrial tubulation and biogenesis, including FZO-1/Mitofusin, UNC-43 protein kinase, and DAF-16/FOXO. Importantly, mutation of each of these factors negated lifespan extension in prx-11-defective animals, indicating that pexophagy inhibition promotes longevity only if mitochondrial health is co-maintained. We also found that experimental perturbation of mitochondria precipitated faster pexophagy with aging, implying bidirectionality in signaling between these two organelles. Our data support a model in which peroxisomes and mitochondria track together with age and interdependently influence animal lifespan.

Keywords:  cellular aging; inter-organelle crosstalk; lifespan; mitochondrial tubulation; pexophagy

DOI:  https://doi.org/10.18632/aging.206395
Acta Physiol (Oxf). 2026 Aug;242(8): e70276

Mitoquinone Prevents Cardiac Dysfunction by Normalizing Mitochondrial ROS and Calcium Handling in Acute Myocardial Infarction.

Carolina Falcão Ximenes, Pietra Zava Lorencini, Carmen Castardeli, Marlon Ramos Rosado Machado, Katyana Kaline Silva Ferreira, Sara Bianca Oliveira Mendes, Anna Karolina Nascimento Costa, Mario Morais Silva, Sérgio Ricardo Aluotto Scalzo, Marcos Eliezeck, Silvia Guatimosim, Eduardo Hertel Ribeiro, Donald M Bers, Aurélia Araujo Fernandes, Ivanita Stefanon.

  Acute myocardial infarction (MI) is the leading cause of heart failure (HF). However, the role of mitochondrial ROS (ROSm) in early MI dysfunction remains unclear. This study aimed to evaluate the impact of MitoQ on cardiac function in cases of heart HF following MI. Male Wistar rats were divided into four experimental groups: Sham, Infarct, Sham+MitoQ, and Infarct+MitoQ. MitoQ was administered orally (8 mg/kg/dia) for 7 days. Hemodynamic parameters, infarct area, papillary muscle contractility, cardiomyocyte mechanics, Ca2+ transients, and total and mitochondrial superoxide (DHE and MitoSOX) were assessed. After 7 days of MI, rats exhibited impaired contractility, altered inotropic response to extracellular Ca2+, cardiomyocyte hypertrophy, and increased total and ROSm. MitoQ prevented body weight loss and significantly improved hemodynamic parameters compared to the Infarct group. In papillary muscles, MitoQ restored basal isometric force and the inotropic response to extracellular Ca2+. In cardiomyocytes, it attenuated hypertrophy, preserved shortening, and reduced ([Ca2+]i) transient amplitude. MitoQ significantly decreased total and mitochondrial O2•- production. It selectively reduced NOX1 expression under simulated conditions but did not significantly affect NOX2, SOD1, or catalase expression in the context of MI. MitoQ prevented contractile dysfunction, suggesting that mitochondrial oxidative stress plays a decisive role in myocardial dysfunction during the acute phase of MI. Targeting antioxidant therapy to the mitochondria represents a promising strategy for preventing post-infarction heart failure and opens new perspectives for the development of more effective interventions in the treatment of cardiovascular diseases.

Keywords:  mitochondria; myocardial contractility; myocardial infarction; oxidative stress; reactivity oxygen species

DOI:  https://doi.org/10.1111/apha.70276
bioRxiv. 2026 Jul 01. pii: 2026.06.29.734522. [Epub ahead of print]

Cardiovascular Benefits of Menopause Hormone Treatment is Age-Dependent.

Cassandra D Lalisan, Connor Gavin, Bridget Litts, Jeffrey A Rein, Julia An, Min Zhong, Rajguru Boobalan, Yu Wang, Amelia Van Aelst, Sivaprakasam Chinnarasu, Yaomin Xu, MacRae Linton, John M Stafford, Lin Zhu.

Background: Hormone therapy (HT) has not consistently reduced atherosclerotic cardiovascular disease (ASCVD) events in post-menopausal women, yet the underlying mechanisms remain poorly understood.
Methods: Female Ldlr -/- mice with established atherosclerosis were subjected to surgical menopause and treated with 17β-estradiol (E 2 ) following lipid normalization. Studies were performed in aging and young mice. To determine whether inflammation mediates the age-dependent response to HT, a cohort of aging mice underwent transplantation with Ifnγ -/- bone marrow (BM) before hormone treatments. Metabolic parameters, HDL function, systemic inflammation, atherosclerotic burden, liver metabolic and oxidative stress signaling, and hepatic estrogen receptor signaling were evaluated.
Results: In aging mice, menopause E 2 treatment failed to reduce established atherosclerosis as shown in sham operated mice during lipid normalization. Instead, E 2 treatment increased circulating IFNγ and IL-6, impaired HDL antioxidant and cholesterol efflux functions, and promoted inflammatory and vulnerable plaque phenotypes. Suppression of inflammation through Ifnγ -/-BM transplantation restored HDL function and significantly reduced atherosclerosis in E 2 -treated aging mice. In contrast to aging mice, young mice exhibited reduced systemic and plaque inflammation, improved HDL functions and atherosclerosis following E 2 treatment. Liver RNA sequencing and qPCR validation identified activation of inflammatory, oxidative stress, and lipid metabolic pathways in aging E 2 -treated mice, which were largely attenuated following Ifnγ -/- bone marrow transplantation as well as in young mice. Compared to young mice, aging mice presented hepatic estrogen receptor remodeling characterized by reduced estrogen receptor α (ERα) expression and increased G-protein coupled estrogen receptor (GPER) expression. Constitutive GPER activation was accompanied by induction of NOX1-dependent oxidative stress, which was further exacerbated by E 2 treatment, leading to persistent inflammation.
Conclusions: The cardiovascular effects of estrogen therapy are fundamentally age dependent. Aging shifts estrogen signaling toward hepatic oxidative stress and inflammation through increased GPER. While E 2 treatment preserves both metabolic and cardiovascular protection in young mice, aging exacerbates GPER-NOX1-mediated oxidative stress, resulting in impaired HDL function and persistent residual ASCVD risk. These findings identify inflammation-driven, non-lipid mechanisms as potential therapeutic targets to improve cardiovascular outcomes during hormone therapy in postmenopausal women.

DOI: https://doi.org/10.64898/2026.06.29.734522
Mol Neurobiol. 2026 Jul 10. pii: 753. [Epub ahead of print]63(1):

SUMOylation in Mitochondrial Quality Control: Mechanisms and Implications for Neurodegenerative Disease.

Qingya Wu, Dengying Fan, Jianhui Ren, Yafang Xing, Zhengzheng Chen, Haochen Jin, Yisheng Lu, Xiaopeng Wang, Hua Zheng.

  Mitochondria, as the primary energy-generating organelles in neurons, play a pivotal role in regulating cellular metabolism. Given the post-mitotic nature and long lifespan of neurons, they are particularly vulnerable to the cumulative burden of mitochondrial damage. In response to various physiological and stress signals, a sophisticated mitochondrial quality control (MQC) system has evolved, which encompasses mitochondrial biogenesis, dynamics (fission and fusion), and mitophagy. This coordinated network acts as a critical surveillance mechanism to eliminate damaged components and maintain a healthy mitochondrial pool. The small ubiquitin-like modifier (SUMO) pathway, involving reversible SUMOylation and deSUMOylation, has emerged as a key regulator of MQC by directly modifying its core components. Dysregulation of the SUMO pathway disrupts mitochondrial homeostasis, and the resulting mitochondrial dysfunction is increasingly recognized as a central pathogenic mechanism in neurodegenerative diseases. This review systematically examines the role of the SUMO pathway in regulating MQC and its implications in the pathogenesis of Alzheimer's disease, Parkinson's disease, and Huntington's disease. Finally, we discuss the therapeutic potential and translational challenges of targeting the SUMO pathway for the treatment of neurodegenerative diseases.

Keywords:  Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy; Neurodegenerative diseases; SUMOylation

DOI:  https://doi.org/10.1007/s12035-026-06050-0
Inflammopharmacology. 2026 Jul 08.

Regulation of NLRP3 inflammasome signaling in Alzheimer's disease: emerging neuroprotective role of phytochemicals.

Aditi Gupta, Shivraj Singh, Tryambak Deo Singh.

  The Nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is a multiprotein complex that plays an important role in neuroinflammatory diseases, including Alzheimer's disease (AD). NLRP3 inflammasome activation involves upstream priming and activation signals, including amyloid-β aggregates, mitochondrial dysfunction, and oxidative stress, which promote inflammasome assembly and trigger downstream effector responses. This leads to caspase-1 activation and cleavage of GSDMD and the subsequent release of pro-inflammatory cytokines such as IL-1β and IL-18, thereby amplifying neuroinflammation and contributing to the neuronal damage characteristic of AD. Two known pathways of NLRP3 inflammasome activation are the canonical pathway, mediated by caspase-1, and the non-canonical pathway, mediated by caspase-11 (in mice) or caspase-4/5 (in humans). The use of phytochemicals to prevent NLRP3 inflammasome activation offers potential to reduce neuroinflammation and maintain neuronal integrity in AD. Phytochemicals such as resveratrol, ginkgolide B, and saffron, among others, have been shown to modulate the activity of the NLRP3 inflammasome through various mechanisms, including the inhibition of NLRP3 assembly, suppression of inflammasome priming signals, and regulation of downstream signaling pathways. Overall, phytochemicals that target NLRP3 inflammasome activation may offer potential benefits for AD management by attenuating neuroinflammation and protecting against neuronal damage.

Keywords:  Alzheimer’s disease; Caspase; Interleukin; NLRP3 inflammasome; Neuroinflammation; Phytochemicals

DOI:  https://doi.org/10.1007/s10787-026-02324-0
Am J Physiol Renal Physiol. 2026 Jul 08.

Eight Weeks of MitoQ Supplementation Does Not Alter Kidney Function or Urinary Kidney Injury Biomarkers in Middle-Aged and Older Adults.

Nina L Stute, Jake P Muma, Zach J Hutchison, Meral N Culver, Braxton A Linder, Sofia O Sanchez, Danielle L Kirkman, Orlando M Gutierrez, Andreas N Kavazis, Austin T Robinson.

  Introduction: Several human trials have used the mitochondrial antioxidant mitoquinol mesylate (MitoQ). There are no apparent negative consequences on the kidneys following an acute high dose of MitoQ in young adults, however it remains unclear whether chronic MitoQ influences kidney function. Therefore, we examined whether eight weeks MitoQ supplementation (20mg/day) impacts kidney function and kidney injury biomarkers using a randomized, placebo-controlled, crossover study in middle-aged and older adults (n=30, 8 males/22 females, 57±8 years). Methods: Participants completed four visits (pre- and post-placebo; pre- and post-MitoQ) where we collected serum samples (creatinine and cystatin c) and 24-hr urine samples to assess general kidney function (estimated glomerular filtration rate [eGFR] and creatinine clearance), and kidney injury markers (neutrophil gelatinase-associated lipocalin; NGAL, kidney injury molecule-1; KIM-1, nephrin, tissue inhibitor of metalloproteinase-2; TIMP-2, and insulin-like growth factor binding protein-7; IGFBP7). We used mixed-effects models to examine time, condition, and interaction effects. Results: We observed no alterations in glomerular filtration measures (ps ≥ 0.309), or kidney injury markers when indexed to flow rate, osmolality, or creatinine (ps ≥ 0.198). For example, TIMP-2 × IGFBP7 was not different between groups (pre placebo: 114 ± 162, post placebo: 138 ± 161; pre MitoQ: 162 ± 238, post MitoQ: 127 ± 137 ng2/min; interaction p = 0.754). Conclusion: Eight weeks of MitoQ supplementation doesn't appear to benefit or harm kidney function or kidney injury markers in middle-aged and older adults.

Keywords:  Acute Kidney Injury; Antioxidants; Chronic Kidney Disease; Dietary Supplements; Mitochondrial Reactive Oxygen Species

DOI:  https://doi.org/10.1152/ajprenal.00174.2026
bioRxiv. 2026 Jul 02. pii: 2026.06.29.735215. [Epub ahead of print]

N-Acetylaspartate Synthesis as a Thermodynamic Relief Mechanism for Mitochondrial Aspartate Aminotransferase.

Narayanan Puthillathu, John R Moffett, Barbara S Slusher, Aryan M Namboodiri.

N-acetylaspartate (NAA) is the most abundant neuron-enriched acetylated metabolite in the mammalian brain, but its metabolic purpose remains unresolved. We developed a simplified kinetic model of mitochondrial aspartate metabolism to test whether NAA synthesis by aspartate N-acetyltransferase (ASPNAT) acts as a thermodynamic "relief valve" for mitochondrial aspartate aminotransferase (AAT) under the low-oxaloacetate (OAA) conditions expected in neuronal mitochondria. In the mitochondrial-compartment model, ASPNAT lowered steady-state mitochondrial aspartate from 141 to 105 µ M and increased net forward AAT flux by 30.9%. The relative AAT-relief effect was largest when OAA and aspartate-glutamate carrier 1 (AGC1/Aralar1)-mediated export were both low, whereas acetyl-CoA availability controlled the substrate-supported capacity for NAA synthesis. That places the relief effect in a narrow regime where product removal matters most. ASPNAT titration produced a graded, concentration-dependent response rather than a binary on/off response. Energetic comparisons showed that the gain in AAT-linked support comes at a modest acetyl-CoA cost, which makes NAA synthesis easier to sustain in carbon-replete states than in carbon-poor ones. Some studies have suggested a secondary cytoplasmic site of NAA synthesis, and we therefore examined how the network response changed with a change in ASPNAT topology. Mitochondrial matrix ASPNAT increased forward AAT flux by 53.32%, whereas cytoplasmic ASPNAT decreased ASPNAT flux by 17.8%. Allowing OAA to vary preserved the positive ASPNAT-dependent relief of AAT flux, but because this simplified extension produced unrealistically low absolute fluxes, it is interpreted as a robustness check on the direction of the mechanism rather than as a prediction of physiological metabolic rates. These results identify mitochondrial NAA synthesis as a plausible thermodynamic relief valve for mitochondrial AAT and define a directional prediction that could test whether severe metabolic stress reroutes effective ASPNAT-linked aspartate metabolism.

DOI: https://doi.org/10.64898/2026.06.29.735215
Proc Natl Acad Sci U S A. 2026 Jul 14. 123(28): e2530907123

Dopamine-driven mitochondrial reverse electron transport in immune cells mediates gut-brain ROS signaling during sleep deprivation.

Yan Zhang, Jae-Hyuk Lee, Ziqi Yu, Yinrui Tao, Suman Rimal, Yanzi He, Lei Lv, Bingwei Lu, Yong Ping.

  Sleep deprivation (SD), together with inevitable stress inherent to conventional SD protocols, can induce oxidative stress and inflammation, thereby increasing the risk of premature death. However, the source and signaling pathways underlying reactive oxygen species (ROS) generation remain unclear. Here, we demonstrate that both mechanical and thermogenetic SD, along with possible stress induced by both protocols, lead to initial ROS accumulation in Drosophila gut subregions, including the proventriculus (PV) and PV-resident hemocytes, via upregulation of dopamine (DA) biosynthesis. Intriguingly, DA acts unconventionally by activating mitochondrial reverse electron transfer (RET), presumably through modifying interactions between the respiratory complex I proteins NDUFV1 and NDUFS3. RET-ROS elicits hemolymphatic IMD/Relish-mediated antibacterial defense. However, during chronic SD, downregulation of the Drosophila APOE/D ortholog Neural Lazarillo promotes the recruitment of hemocytes to the central brain and, together with this process, leads to widespread neuronal ROS accumulation in an Alzheimer's disease (AD) fly model. Inhibiting RET or hemocytic DA levels extends the survival of animals under chronic SD. Our work reveals DA-driven RET-ROS in innate immune cells during SD, highlights the pivotal role of a gut-innate immune-brain crosstalk in mediating the effect of SD manipulation on aging and AD pathogenesis, and suggests ways to lessen the consequence of SD, a profound health issue in modern society.

Keywords:  dopamine; mitochondria; reactive oxygen species; sleep

DOI:  https://doi.org/10.1073/pnas.2530907123
Cell Rep. 2026 Jul 04. pii: S2211-1247(26)00681-9. [Epub ahead of print]45(7): 117603

A cold-induced GDF15-secreting adipocyte subpopulation regulates energy homeostasis through endocrine signaling.

Chunyan Wu, Tongtong Wang, Songlin Gong, Jing Zhang, Charlotte G Mann, Min Li, Ziyu Liu, Yizhi Sun, Shenwei Shi, Zhenghong Liu, Katrien De Bock, Miroslav Balaz, John Speakman, Christian Wolfrum.

  Brown adipose tissue (BAT) regulates whole-body energy balance through uncoupling protein 1 (UCP1)-dependent thermogenesis and secretion of metabolic factors. Recent studies suggest UCP1-independent mechanisms contribute to energy balance, with UCP1 being conditionally dispensable. However, how adaptation to UCP1 deficiency is regulated remains unclear. Our single-nucleus RNA sequencing of BAT from cold-exposed Ucp1 knockout mice reveals a distinct brown adipocyte subpopulation (U2). U2 adipocytes exhibit a secretory profile enriched in batokines like growth differentiation factor 15 (GDF15), suggesting a shift toward an endocrine role. Functional analyses reveal that GDF15-GFRAL signaling is required to sustain energy expenditure in adipose tissue (AT). The Ucp1/Gfral knockout increased food intake to compensate for decreased energy expenditure in AT. Additionally, a conserved UCP1-GDF15 regulatory axis in human AT is observed. These findings identify a regulatory brown adipocyte subpopulation emerging in response to UCP1 deficiency, representing a compensatory mechanism for maintaining energy homeostasis in mammals.

Keywords:  CP: metabolism; GDF15; GFRAL; Ucp1 knockout mice; adipose tissue; cold exposure; energy expenditure; single-nucleus RNA sequencing

DOI:  https://doi.org/10.1016/j.celrep.2026.117603
Mol Biol Rep. 2026 Jul 10. pii: 1146. [Epub ahead of print]53(1):

Nicotinamide mononucleotide ameliorates high glucose/high fat-induced cardiomyocyte metabolic dysfunction through SIRT1-mediated CPT1A stabilization.

Meinv Huang, Zhan Wang, Lishan Zeng, Lifan Zheng, Meifang Wu, Xi Chen.

   OBJECTIVE: To investigate the mechanism of nicotinamide mononucleotide (NMN) in ameliorating high glucose/high fat (HG/HF)-induced metabolic dysfunction in diabetic cardiomyopathy (DCM) through SIRT1-mediated CPT1A stabilization.
METHODS: DCM cellular model was established using H9c2 cell. After screening optimal NMN concentration via cell counting kit-8 (CCK-8) assay and Western blot, cellular viability, apoptosis, total reactive oxygen species (ROS), mitochondrial function, ATP, and β-hydroxybutyrate (β-OHB) content were measured. The molecular interplay among NMN-SIRT1-CPT1A was further elucidated through co-immunoprecipitation (Co-IP), cycloheximide (CHX) chase assay, MG132 rescue, and CPT1A K675R mutation.
RESULTS: HG/HF reduced H9c2 cells viability by 26.66% and SIRT1 protein expression by 79.30%, both of which were restored by 100 µM NMN. In vitro, NMN enhanced cell viability, suppressed apoptosis and total ROS, stabilized mitochondrial function, and increased ATP and β-OHB content, these protective effects were attenuated by SIRT1 knockdown. Western blot analysis demonstrated NMN upregulated CPT1A and CD36 expression by activating SIRT1. Co-IP revealed that HG/HF markedly elevated the acetylation and ubiquitination of CPT1A, both of which were weakened by NMN treatment. Moreover, SIRT1 directly interacted with CPT1A and deacetylated CPT1A via the proteasomal pathway, thereby blocking its ubiquitination. Additionally, the K675R point mutation further confirmed Lys675 as the specific deacetylation target of SIRT1 on CPT1A.
CONCLUSION: NMN activates SIRT1 to deacetylate CPT1A at Lys675, inhibiting its degradation and enhancing mitochondrial ATP and β-OHB generation, thereby mitigating HG/HF-induced injury. These findings provide SIRT1-mediated CPT1A stabilization as a potential therapeutic target for DCM.

Keywords:  Acetylation; CPT1A; Diabetic cardiomyopathy; Nicotinamide mononucleotide; SIRT1; Ubiquitination

DOI:  https://doi.org/10.1007/s11033-026-12332-6
Ageing Res Rev. 2026 Jul 10. pii: S1568-1637(26)00244-8. [Epub ahead of print]121 103252

Mitochondrial-ER stress crosstalk in osteoarthritis: From ageing-associated chondrocyte dysfunction to emerging therapeutics.

Md Meraj Ansari, Godagama Gamaarachchige Dinesh Suminda, Rehan Khan, Young-Ok Son.

  Osteoarthritis (OA) is a common age-associated joint disorder driven not only by mechanical wear but also by progressive intracellular stress, metabolic imbalance, and chronic inflammation that culminate in cartilage degeneration and functional disability. Increasing evidence identifies mitochondrial dysfunction and endoplasmic reticulum stress (ERS) as central pathological hubs regulating chondrocyte survival, extracellular matrix (ECM) integrity, and inflammatory signaling. Mitochondrial impairment promotes excessive reactive oxygen species (ROS) generation, defective ATP production, disturbed mitochondrial dynamics, and inadequate mitophagy, collectively accelerating ECM catabolism and chondrocyte apoptosis. In parallel, ERS activates the unfolded protein response (UPR) to restore proteostasis through the PERK, IRE1α, and ATF6 pathways; however, sustained UPR activation shifts from adaptive signaling to maladaptive outcomes, amplifying inflammation, oxidative injury, and cell death in OA cartilage. Notably, emerging data highlight bidirectional crosstalk between mitochondria and ER, particularly via mitochondria-associated membranes (MAMs), as a key driver of Ca²⁺ dysregulation, inflammasome activation, and degenerative joint remodeling. Therapeutic strategies targeting these stress pathways including mitochondrial antioxidants, NAD⁺-boosting agents, mitophagy modulators, chemical chaperones, and selective UPR regulators have demonstrated potential to attenuate cartilage destruction and restore joint homeostasis. This review synthesizes current mechanistic insights into mitochondrial ERS signaling in OA and critically evaluates evolving disease-modifying interventions aimed at intracellular stress reprogramming. Finally, we discuss translational challenges and future directions for developing precision therapies that exploit organelle stress pathways to improve long-term joint health.

Keywords:  Aging; Endoplasmic reticulum stress; Mitochondrial dysfunction; Osteoarthritis; Oxidative stress; Unfolded protein response (UPR)

DOI:  https://doi.org/10.1016/j.arr.2026.103252
Biogerontology. 2026 Jul 06. pii: 123. [Epub ahead of print]27(4):

Emodin alleviates radiation-induced pulmonary fibrosis by targeting cellular senescence via the mtDNA-cGAS-STING axis.

Wei Duan, Yanling Sha, Xi Tang, Riu Liu, Bin Su, Meijing Huang, Xin Xun, Yunfei Ye.

  Radiation-induced pulmonary fibrosis (RIPF) is a severe complication of thoracic radiotherapy with limited effective treatment options. Cellular senescence has emerged as a critical driver of age-related tissue fibrosis; however, its role in RIPF and potential as a therapeutic target are underexplored. In this study, we investigated whether emodin, a natural compound with known anti-aging properties, alleviates RIPF by suppressing radiation-induced cellular senescence. In a mouse model exposed to 16 Gy thoracic irradiation, emodin treatment significantly attenuated pulmonary fibrosis, reduced collagen deposition, and downregulated fibrotic markers. Notably, emodin markedly suppressed radiation-induced senescence in pulmonary epithelial cells, accompanied by reduced secretion of senescence-associated secretory phenotype (SASP) factors. Mechanistically, emodin preserved mitochondrial integrity, curbed mitochondrial reactive oxygen species (mtROS) accumulation, and prevented mitochondrial DNA (mtDNA) leakage into the cytoplasm, thereby inhibiting the cGAS-STING-NF-κB signaling pathway, a key pro-inflammatory axis in senescent cells. Importantly, knockdown of cGAS or treatment with the mitochondrial uncoupler CCCP attenuated the anti-senescent effects of emodin, underscoring the centrality of mitochondrial dysfunction and the mtDNA-cGAS-STING axis in senescence-driven fibrosis. Collectively, these findings identify emodin as a novel senescence-targeting agent that mitigates RIPF by alleviating mitochondrial dysfunction and disrupting the mtDNA-cGAS-STING pathway, highlighting its therapeutic potential in age-related fibrotic diseases.

Keywords:  CGAS–STING pathway; Cellular senescence; Emodin; Mitochondrial dysfunction; RIPF

DOI:  https://doi.org/10.1007/s10522-026-10472-7
Ageing Res Rev. 2026 Jul 07. pii: S1568-1637(26)00237-0. [Epub ahead of print]121 103245

Brain health across the lifespan and the impact of nutrition, exercise, microbiota, and sleep.

Andrew C Shin, Zobayda F Haque, Shannon Galyean, Marleigh Hefner, Mina Esmaeili, J Josh Lawrence, Bruce A Watkins.

  Dietary strategies that support long-term cognitive health and resilience against neurodegenerative diseases are important with aging and senescence. Brain aging is a consequence of intricate biological changes that occur over the lifespan. The process of aging involves the decline in metabolic and physiologic functions, and changes in anatomical structure. However, our lifestyle practices, including diets and nutrient intakes, physical exercise, sleep quality, and cognitive activity can help to minimize the aging effects on the brain. Furthermore, neurodegenerative diseases often have detrimental effects on brain neurons, that show gradual damage leading to compromised cognitive function and impaired body movement. Our review describes the biochemical and physiological changes in brain with advancing age. We introduce several aspects of nutrients (lipids, glucose, vitamins, and protein), dietary factors (flavonoids), and diet practices that afford benefits to reduce the effects of aging on the brain. In addition, many aspects of metabolic dysregulation of macronutrients are described in brain aging. Vital to the lifestyle factors that improve brain health and reduce or delay the negative effects on brain aging are physical exercise and sleep. The importance of brain-derived neurotrophic factors, exerkines, and endocannabinoids are described. Herein is a concise overview of the aging brain, role of nutrition in brain health, importance of nutrition in aging and senescence of the brain, and the systemic actions of physical exercise on brain plasticity and health. Original research with models, clinical studies, and landmark reviews on the topic are cited in our novel and comprehensive approach to nutrition the aging brain.

Keywords:  Aging; Brain; Diet; Health; Neurodegenerative disease; Physical exercise; Plasticity

DOI:  https://doi.org/10.1016/j.arr.2026.103245
Front Nutr. 2026 ;13 1871474

Effects of hesperidin supplementation on inflammation and oxidative stress in overweight or obese individuals: a systematic review and meta-analysis of randomized controlled trials.

Kun Zhu, Wen Li, Tingting Liao, Jianlong Guo, Tingwei Huang, Degui Chang, Yaodong You.

  This study aimed to evaluate, through a systematic review and meta-analysis of randomized controlled trials (RCTs), the effects of hesperidin and hesperidin-containing citrus interventions on biomarkers of inflammation, oxidative stress, and endothelial function in overweight or obese individuals. Two authors independently searched PubMed, Web of Science, Embase, Scopus, and the Cochrane Library from inception to April 4, 2026. Methodological quality was assessed using the Cochrane Risk of Bias 2 tool (RoB 2), and certainty of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Heterogeneity was assessed using Cochran's Q test and the I-square (I 2) statistic, and fixed- or random-effects models were applied as appropriate. Most continuous outcomes were pooled as mean differences (MDs) with 95% confidence intervals (CIs), whereas total antioxidant capacity (TAC) was pooled as standardized mean differences (SMDs; Hedges' g) due to inconsistent assay methods. Sixteen RCTs involving 845 participants were included. Compared with placebo or control, hesperidin-related interventions reduced C-reactive protein/high-sensitivity C-reactive protein (CRP/hsCRP) (MD: -0.43 mg/L, 95% CI: -0.68, -0.17, P = 0.001; GRADE = moderate), tumor necrosis factor-alpha (TNF-α) (MD: -2.84 pg/mL, 95% CI: -4.81, -0.86, P = 0.005; GRADE = very low), and vascular cell adhesion molecule-1 (VCAM-1) (MD: -27.16 ng/mL, 95% CI: -50.13, -4.19, P = 0.020; GRADE = very low), with no significant effects on interleukin-6 (IL-6), TAC, or intercellular adhesion molecule-1 (ICAM-1). Malondialdehyde (MDA) and superoxide dismutase (SOD) were reported narratively in single studies. Current randomized evidence suggests that hesperidin-related interventions are associated with a modest reduction in CRP/hsCRP, representing the most consistent biomarker signal to date. Evidence for TNF-α and VCAM-1 remains very low in certainty, and findings for IL-6, oxidative stress markers, and ICAM-1 remain inconclusive. Marked between-study differences in intervention matrix, design structure, and reporting methods preclude dose- or matrix-specific recommendations at present. Further high-quality randomized trials with longer follow-up, standardized biomarker assessment, and better characterization of formulations are needed.

Keywords:  citrus matrix; hesperidin; inflammation; meta-analysis; obesity; overweight; oxidative stress

DOI:  https://doi.org/10.3389/fnut.2026.1871474
Ann Gen Psychiatry. 2026 Jul 09.

C-reactive protein-triglyceride-glucose index and risk of incident depressive symptoms in older adults: an eight-year follow-up study from ELSA.

Mixue Guo, Mengyuan Cai, Huqiang Dong, Zongren Zhao, Ke Zheng.

   BACKGROUND: Depression is a common mental health issue among older adults, yet few studies have explored whether metabolic biomarkers predicting its onset exist. The CRP-TyG index (CTI), combining C-reactive protein and the triglyceride-glucose index, may more effectively capture inflammatory-metabolic dysregulation than either marker alone. However, prospective evidence on the relationship between CTI and depression in aging populations is limited.
METHODS: We analyzed data from 2,813 depression-free participants aged ≥ 50 years in ELSA, with follow-up through Wave 8. Baseline CTI was assessed from fasting blood biomarkers, and depressive symptoms were evaluated using the CES-D-8 scale. Cox proportional hazards models were used to estimate hazard ratios (HRs). To assess the potential influence of missing data, multiple-imputation analyses were additionally performed as sensitivity analyses.
RESULTS: During follow-up, 136 participants developed incident depressive symptoms. After full adjustment including BMI, each 1-SD increase in CTI was associated with a higher risk of incident depressive symptoms (HR = 1.253; 95% CI: 1.002-1.479; p = 0.035). Multiple-imputation sensitivity analyses yielded directionally consistent results.
CONCLUSION: In this nationally representative cohort of adults aged 50 years and older in England, higher baseline CTI was prospectively associated with an increased risk of incident depressive symptoms. CTI may serve as a scalable biomarker for identifying older adults at elevated risk of depressive symptoms.

Keywords:  CTI; Cohort study; Depressive symptoms; ELSA; Older adults

DOI:  https://doi.org/10.1186/s12991-026-00690-1
Front Cardiovasc Med. 2026 ;13 1797019

Association of age at menopause with cardiovascular disease and mortality:insights from NHANES and a clinical cohort.

Xinmiao Hong, Linxi Jin, Guoli Shang, Qiwei Chen, Zhuang Han, Shuhong Yao, Zhita Wang, Liang Li, Weidong He, Xianpei Heng, Liuqing Yang.

   Background: Age at menopause is closely associated with cardiovascular disease and mortality, whereas the underlying mechanisms remain unclear. This study employed mediation analysis to explore potential pathways underlying this association.
Methods: Natural postmenopausal women were identified from the NHANES database to assess the association between age at menopause and cardiovascular disease and mortality. Mediation analysis was performed to identify potential mediators. A hospital-based cohort was used for a supportive analysis.
Results: Compared with women with menopause at 50-51 years, those with menopause before 40 years had a higher prevalence of cardiovascular disease and increased risks of all-cause and cardiovascular mortality. Dose-response analysis indicated that each one-year decrease in age at menopause was associated with 3%, 3%, and 4% increases in cardiovascular disease prevalence, all-cause mortality, and cardiovascular mortality, respectively. Mediation analysis showed that total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), hypertension, and glycated hemoglobin partially mediated the association between age at menopause and adverse outcomes. A hospital-based cohort study further supported these findings.
Conclusion: Early menopause is significantly associated with higher cardiovascular disease prevalence, all-cause mortality, and cardiovascular mortality, and this association is partially mediated by metabolic dysregulation.

Keywords:  age at menopause; all-cause mortality; cardiovascular disease; cardiovascular mortality; mediation analysis

DOI:  https://doi.org/10.3389/fcvm.2026.1797019
Front Aging. 2026 ;7 1732426

A multi-modal longevity protocol integrating lifestyle, supplements, and autologous pro-regenerative cell-conditioned media: a pilot study.

Esteban Ortega, Guenole Addor, Sonam Bhatia, Max Lewinsohn, Pierre-Edouard Sottas.

   Introduction: Biological aging is a modifiable process contributing to functional decline and chronic disease risk. Multi-modal interventions targeting aging hallmarks have shown promise, yet human data integrating lifestyle, supplementation, and regenerative therapies remain limited.
Methods: This single-arm, open-label pilot trial in 16 healthy adults aged 46-72 (14 completers) tested a 17-week multi-modal program integrating lifestyle optimization, targeted supplementation, and two intravenous infusions of autologous pro-regenerative cell-derived conditioned media (APRC-CM). Trial registration: ClinicalTrials.gov, NCT07322224.
Results: The intervention improved clinical biomarkers and reduced biological-age measures (PhenoAge and an epigenetic DNA-methylation clock) despite the cohort's already healthy baseline (chronological age 59.3 years; PhenoAge 55.5 years; epigenetic age 57.9 years), consistent with a net reversal of biological age rather than merely a correction of age acceleration. PhenoAge declined by 2.0 years (p = 0.014), reaching 5.8 years below chronological age; epigenetic age decreased by 2.7 years (p = 0.003), widening the gap to 4.1 years. Exploratory response analysis revealed heterogeneity, with a larger-response subgroup showing a mean epigenetic-age reduction of 5.1 years versus 0.2 years in a smaller/no-response subgroup. Among baseline biomarkers, serum iron strongly predicted response: lower iron correlated with greater epigenetic-age reduction (r = 0.64; p = 0.013), identifying baseline iron status as a candidate prognostic biomarker of response. No adverse events were reported.
Discussion: Such reductions in health-optimized individuals are notable and may indicate a lowering below expected norms rather than solely a correction of age acceleration. The observed response heterogeneity, together with baseline iron metabolism as a potential predictor of response, is hypothesis-generating and warrants validation in larger, controlled trials, particularly as this open-label, single-arm pilot lacked a control or sham comparator.

Keywords:  age reversal; autologous conditioned media; biological age; epigenetic clock; iron metabolism

DOI:  https://doi.org/10.3389/fragi.2026.1732426
Mol Psychiatry. 2026 Jul 06.

Cognitive and affective effects of L-Theanine: a systematic review and meta-analysis of 31 randomized trials.

Cyril Gerolymos, Elisa Saddier, Laurent Boyer, Guillaume Fond.

BACKGROUND: L-theanine, an amino acid derived from green tea, has been suggested to alleviate affective symptoms and enhance cognitive performance, but its clinical relevance remains uncertain.
METHODS: We conducted a systematic review and meta-analysis of 31 randomised controlled trials (n = 1168) comparing oral L-theanine with placebo in healthy and clinical populations. The primary outcome was the acute effect of a single dose on stress in healthy adults. Secondary outcomes included clinical measures (stress after repeated dosing, anxiety, depressive symptoms, and fatigue) and cognitive measures (reaction times and attention tasks with single and repeated doses). Safety was assessed by comparing dropout rates and reasons between L-theanine and placebo groups.
RESULTS: A single 200 mg dose taken 30-60 min before cognitive testing significantly improved choice reaction time (Standardised Mean Difference [SMD] = 0.51; 95% CI, 0.25-0.77), indicating enhanced attention. The reduction in acute stress was modest (SMD = 0.31) and largely influenced by studies with a high risk of bias. No significant effect on fatigue was observed. Excluding one outlier, a significant reduction in depressive symptoms following a single dose in healthy individuals was found (SMD = 0.69; 95% CI, 0.13-1.25) with low heterogeneity. Anxiety effects were inconsistent and non-significant except for one study on psychotic anxiety (SMD = 0.54; 400 mg/day for 8 weeks). No serious adverse events were reported.
CONCLUSIONS: L-theanine is safe and shows a robust short-term benefit on attention in healthy adults, with a potential antidepressant effect warranting confirmation in high-quality trials, especially in clinical populations.

DOI: https://doi.org/10.1038/s41380-026-03727-9
Front Pharmacol. 2026 ;17 1831343

The special extract ERr 731® from the root of rhapontic rhubarb (Rheum rhaponticum): efficacy in headache/migraine and further climacteric complaints in women in the perimenopause.

Peter W Heger, Ilka Meinert, Dirk Hotz.

   Background: Menopause is associated with neuroendocrine changes and a variety of climacteric symptoms. While hormone replacement therapy (HRT) remains a standard treatment, safety concerns increase global interest in non-hormonal alternatives like ERr 731®, an extract from Rheum rhaponticum to alleviate climacteric complaints.
Objective: To evaluate the long-term effectiveness of ERr 731® in reducing menopausal climacteric symptoms during a 12-week randomized controlled (RCT) trial followed by a 52-week open-label observational study (OS).
Methods: One hundred and twelve perimenopausal women (aged 45-55 years) with climacteric complaints (Menopausal Rating Scale (MRS) ≥18) participated in this RCT while eighty-nine of these study participants continued in the OS. During the RCT patients received either ERr 731® (4 mg daily) or a placebo. During the OS, all participants received ERr 731® and were assessed every 13 weeks for headache/migraine, dizziness, paresthesia, fluor vaginalis, and general well-being. Descriptive statistics and exploratory t-tests compared symptom severity between day 0 and day 84 as well as day 364.
Results: During the RCT, climacteric complaints were significantly reduced in the ERr 731® group compared to placebo. Symptom severity also decreased across all domains from baseline to week 52 of the OS. Headache/migraine and paresthesia improvements were notable. Since all participants received ERr 731® during the OS, no significant differences between the prior ERr 731® and placebo groups were present (p > 0.05). Dizziness reduction remained significant between groups (p = 0.0086). General well-being improved markedly, with >90% of participants reporting to be "good" or "very good spirits" at week 52.
Conclusion: ERr 731® demonstrated sustained symptom relief and improved well-being over 52 weeks, supporting its role as a non-hormonal option for managing climacteric complaints in perimenopausal women.

Keywords:  ERr 731®; Rheum rhaponticum; menopause; non-hormonal treatment; rhapontic rhubarb extract; vasomotor symptoms

DOI:  https://doi.org/10.3389/fphar.2026.1831343