bims-mistre 2026-06-21 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–06–21
25 papers selected by
Ellen Siobhan Mitchell, MitoQ

Mitochondria and brain aging: From cell-specific dysfunction to intercellular cooperation.
Ovarian-derived signals reprogram hepatic lipid metabolism in aging: Implications for therapeutic targeting of metabolic dysfunction.
APOE4 accelerates menopause-associated brain metabolic shift and disrupts bioenergetic adaptation.
APOE4 negates the effects of ovarian hormones on cerebrovascular endothelial and mitochondrial function.
The lactate shuttle in ageing: a metabolic bridge between muscle fatigue and brain resilience.
Anticancer Therapeutic Potential of Mitochondria-Targeted Antioxidants Against N-Nitrosodiethylamine-Induced Hepatocarcinogenesis.
Fucoxanthin Promotes Longevity and Neuroprotection in Caenorhabditis elegans via DAF-16 and Autophagy Pathways.
Mitochondrial remodeling in obesity: mechanistic links to impaired energy metabolism and therapeutic perspectives.
Mealtime irregularity is associated with higher serum growth differentiation factor-15 levels in older adults: the explanatory role of dietary quality.
Antiaging Effects of Mannose-6-Phosphate through Enhanced Mitochondrial Function and Collagen Remodeling.
Ketone metabolism at the interface of atherosclerosis and brain dysfunction.
Oleuropein and hydroxytyrosol enhance mitochondrial function and biogenesis in SH-SY5Y cells through estrogen-like mechanisms.
Taurine supplementation at the crossroads of metabolism, inflammation and aging: mechanistic and nutritional perspectives.
Age-related arterial stiffness and cerebrovascular dysfunction in mice correlate with cognitive impairment but are not reduced with long-term ALT-711 treatment.
Effects of carnosine supplementation on physical endurance: a placebo-controlled randomized clinical trial.
Beneficial vascular effects of oral phosphatidylserine supplementation in type 2 diabetes.
cGAS-STING signaling pathway: a central pathological mechanism and emerging therapeutic target for postoperative cognitive dysfunction.
Turning back time: a comprehensive list of interventions that decrease next-generation epigenetic aging clocks in humans.
Aging Impairs Macrophage Phagocytosis Through Mitochondrial ROS-Induced Collagen Production.
Probiotic Lactobacillus Reuteri KUB-AC5 Provides Cardioprotection via Mitigating Cardiac Mitochondrial Dysfunction in Obese Rats.
Mitochondrial peptide MOTS-c suppresses systemic and cardiac inflammasome activation in a diabetic rat model.
Repurposing citicoline for single prolonged stress-induced behavioral and hippocampal molecular abnormalities in male mice: novel mechanistic attenuation of endoplasmic reticulum stress, mitochondrial dysfunction, oxidative stress, and apoptosis.
Targeting Mitochondrial Dysfunction With Elamipretide (SS-31) Improves Skeletal Muscle Performance in a HFpEF Rat Model.
Oral L-ergothioneine supplementation in women with suboptimal ovarian reserve: a single-center, open-label, self-controlled pilot study of ovarian reserve markers, endocrine profiles, and reproductive aging-related symptoms.
Chronological age is differentially associated with cognitive performance according to climacteric stage: evidence from a Bayesian multivariate analysis in Chilean women.

Neuron. 2026 Jun 16. pii: S0896-6273(26)00371-5. [Epub ahead of print]

Mitochondria and brain aging: From cell-specific dysfunction to intercellular cooperation.

Amandine Grimm, Undine Lang, Anne Eckert.

  Mitochondria are essential for brain energy metabolism and are increasingly recognized as key contributors to brain aging. Although neurons are exceptionally vulnerable to age-related mitochondrial decline, emerging evidence reveals that glial and vascular cells also exhibit distinct mitochondrial impairments. This review synthesizes recent advances in our understanding of mitochondrial dysfunction across specific brain regions and diverse cell types, highlighting subcellular compartmentalization and metabolic rewiring. We further explore intercellular mitochondrial transfer as a novel form of metabolic cooperation, as well as the therapeutic potential of mitochondrial transplantation. Finally, we highlight recent clinical trials evaluating mitochondria-targeted interventions aimed at preserving brain function in older adults. Together, these findings reposition mitochondria as both integrators and amplifiers of brain aging processes across diverse cell populations. By broadening the focus beyond neurons and emphasizing translational efforts, we offer a comprehensive framework for understanding and therapeutically targeting mitochondrial dysfunction in age-related cognitive decline and neurodegeneration.

Keywords:  aging; astrocytes; blood-brain barrier; brain; intercellular mitochondrial transfer; microglia; mitochondria; mitochondrial transplantation; neurons; oligodendrocytes

DOI:  https://doi.org/10.1016/j.neuron.2026.04.048
Adv Transl Res. 2026 May 08.

Ovarian-derived signals reprogram hepatic lipid metabolism in aging: Implications for therapeutic targeting of metabolic dysfunction.

Nathan D McCoy, Michael T Kinter, Augusto Schneider, Fabiola Santos, Michal M Masternak, Jeffrey B Mason.

   Background and Aim: Aging in mammals is a complex, multifaceted process involving the progressive decline of physiological functions, in which energy metabolism plays a pivotal role. β-oxidation-the primary pathway for converting fatty acids into energy-is tightly linked to aging and to female reproductive senescence. In the present study, we investigated how ovarian tissue remodels hepatic proteins central to the β-oxidation pathway.
Methods: Liver proteomes were analyzed in CBA/J control mice at 4, 13, 23, and 27 months of age and compared with those of 23-month-old mice that received transplants of young ovarian tissue at 13 months. β-oxidation proteins were quantified using high-resolution mass spectrometry. Serum triglycerides were measured enzymatically, and metabolic cage analyses were performed to assess substrate utilization and energy balance.
Results: Ovarian tissue transplantation substantially modulates the expression of β-oxidation-related proteins and reduces systemic lipid accumulation in aged mice. These proteomic shifts are consistent with enhanced metabolic efficiency and decreased oxidative stress-mechanisms well-established as drivers of extended health span and longevity. Results apply to menopause dyslipidemia, insulin resistance, metabolic syndrome, NAFLD, and aging. Transplants reduce β-oxidation proteins and triglycerides, improving hepatic lipid clearance and steatosis risk. Identifying ovarian signals enables non-surgical mimics via peptides or modulators. Changes align with PPARα agonists, CPT1 modulators, mitochondria-targeted antioxidants (MitoQ), and NAD+/sirtuin pathways-offering testable routes to replicate ovarian benefits.
Conclusions: Ovarian-derived signals induce metabolic reprogramming in aged mice, characterized by reduced β-oxidation protein expression, decreased triglyceride accumulation, and improved metabolic efficiency. These findings provide a molecular framework for understanding how ovarian-derived factors may govern metabolism and organismal health during aging, with potential implications for interventions targeting age-related metabolic decline.

Keywords:  PPARα signaling; aging; hepatic metabolism; lipid metabolism; menopause; metabolic reprogramming; ovarian transplantation; pharmacological mechanisms; triglycerides; β-oxidation

DOI:  https://doi.org/10.1556/1661.2026.00112
Front Aging Neurosci. 2026 ;18 1796680

APOE4 accelerates menopause-associated brain metabolic shift and disrupts bioenergetic adaptation.

Tian Wang, Yuan Shang, John W McLean, Fei Yin, Roberta Diaz Brinton.

   Introduction: Disruption of brain glucose and lipid metabolism contributes to Alzheimer's disease (AD) and often emerges before clinical symptoms. Women are at increased AD risk due to menopause-associated estrogen decline, which impairs mitochondrial function and glucose metabolism. Women's risk of AD is further exacerbated by the APOE4 allele, the strongest genetic risk factor for late-onset AD.
Methods: To investigate the impact of APOE genotype on the menopausal metabolic transition, brain metabolomic and lipidomic profiling was conducted in humanized female APOE3/3, APOE3/4, and APOE4/4 mice across chronological and endocrinological stages from pre- to postmenopause.
Results: APOE3/3 mice exhibited dynamic regulation of metabolic systems that supported postmenopausal brain bioenergetic demand. In contrast, APOE3/4 and APOE4/4 mice exhibited accelerated and compromised metabolic adaptation, resulting in postmenopausal amino acid depletion, reduced tricarboxylic acid (TCA) cycle intermediates, lipid accumulation, and compromised brain lipid composition. A single APOE4 allele was sufficient to impair metabolic adaptation, while APOE4 homozygosity resulted in greater severity of deficits.
Discussion: Outcomes of these analyses revealed that APOE4 accelerated menopause-related metabolic decline and compromised bioenergetic adaptation, providing a mechanistic basis for increased AD susceptibility and earlier onset in APOE4-positive women.

Keywords:  APOE4; Alzheimer’s; brain; menopause; metabolism; women’s health

DOI:  https://doi.org/10.3389/fnagi.2026.1796680
J Physiol. 2026 Jun 19.

APOE4 negates the effects of ovarian hormones on cerebrovascular endothelial and mitochondrial function.

Mackenzie N Kehmeier, Alexandra Famiano, Abigail E Cullen, Thomas Leonhardt, Skylyn J Ferguson, Madeleine Snyder, Carrie E McCurdy, Daniel J Tyrrell, Nabil J Alkayed, Ashley E Walker.

  The APOEε4 allele and oestrogen deficiency independently predispose females to an increased risk of vascular and metabolic impairments, but their cerebrovascular effects are less understood. The purpose of this study was to determine the interaction between APOE genotype and oestrogen on cerebrovascular endothelial and mitochondrial function. We studied young female homozygous APOEε3 and APOEε4 mice (n = 19-20/group; ∼6 months old) that were fed a high-fat diet and were ovariectomized (OVX), OVX and supplemented with 17β-oestradiol, or left intact. In APOEε3 mice, OVX was associated with impaired posterior cerebral artery endothelium-dependent dilatation, which was rescued by 17β-oestradiol. However, in APOEε4 mice, there was no effect of OVX or 17β-oestradiol on cerebral artery endothelial function. Carotid artery passive stiffness was greater with OVX and lower with 17β-oestradiol treatment in APOEε3 mice, but there was no impact of OVX or 17β-oestradiol in the APOEε4 mice. In cerebral arteries and arterioles, 17β-oestradiol led to higher mitochondrial complex I respiration in APOEε3 but not APOEε4 mice. These functional differences were concomitant with group differences in mitochondrial DNA copy number, antioxidant enzymes and pro-inflammatory factors. Overall these results indicate that the APOE genotype modulates the impact of OVX and oestradiol on the cerebral vasculature. We found that 17β-oestradiol enhances cerebrovascular endothelial and mitochondrial function in OVX APOEε3 mice but not in APOEε4 mice. This suggests that 17β-oestradiol supplementation may have more cerebrovascular benefits for APOEε4 non-carriers. KEY POINTS: Females have twice the risk of Alzheimer's disease than males, and the APOEε4 genetic variant has a greater risk for Alzheimer's disease than the APOEε3 variant. The risk for Alzheimer's disease increases after menopause in females, suggesting that the loss of female sex hormones may play a role. There are highly inconsistent results among past studies examining the interaction between APOE genotype and oestrogens on brain outcomes, and their impact on the vasculature has not been studied. We aimed to determine the impact of APOEε4 genotype on the cerebrovascular response to ovariectomy and oestradiol. We found that oestradiol improved cerebral artery endothelial function and mitochondrial respiration in ovariectomized APOEε3 mice following ovariectomy. In contrast APOEε4 mice were resistant to the beneficial effects of ovarian hormones on cerebrovascular and mitochondrial function. This research suggests that APOE genotype may be a consideration when weighing the risks and benefits of prescribing hormone replacement therapy to postmenopausal females.

Keywords:  APOE genotype; cerebral artery; endothelium‐dependent vasodilatation; mitochondrial respiration; oestrogen

DOI:  https://doi.org/10.1113/JP290852
Front Physiol. 2026 ;17 1823430

The lactate shuttle in ageing: a metabolic bridge between muscle fatigue and brain resilience.

Yu Zhang, Wenyi Yang, Chunlan Tian.

  Traditionally, lactate was considered a glycolytic byproduct that causes muscle fatigue, but now its biological role is undergoing a significant paradigm shift. Emerging evidence suggests that lactate acts as an inter-organ metabolic and signaling mediator linking exercise-induced peripheral metabolic stress to central nervous system adaptation. This review explores how exercise drives lactate pulses and delivers them to the brain through the circulatory system and blood-brain barrier (BBB). Lactate has a dual function in the brain, serving not only as the preferred energy substrate for active neurons but also as a core signaling molecule. Through pathways involving G protein coupled receptor 81 (GPR81) and histone lactylation, lactate regulates neuroplasticity, cerebrovascular function, neuroinflammation, and antioxidant defense, thereby establishing cognitive resilience. During aging, multiple components of this proposed lactate signaling axis may become compromised, including skeletal muscle lactate production, circulatory and blood-brain barrier transport, and cellular responsiveness within the brain. Such multi-level impairment may contribute to neuromuscular co-aging and may increase vulnerability to neurodegenerative disorders, including Alzheimer's disease. Ultimately, we explored the translational potential of restoring the lactate signaling axis through multimodal strategies to promote healthy aging, including precise exercise prescriptions, GPR81 targeted therapy, metabolic interventions, and biomarker development. This review aims to combine metabolic science with evidence of neuroaging, providing a new theoretical framework for determining the primacy of exercise-driven brain health and advancing anti-aging interventions.

Keywords:  GPR81 receptor; aging; blood-brainbarrier; exercise; histone lactylation; lactate; lactate shuttle; neurodegenerative diseases

DOI:  https://doi.org/10.3389/fphys.2026.1823430
Cell Biochem Funct. 2026 Jun;44(6): e70245

Anticancer Therapeutic Potential of Mitochondria-Targeted Antioxidants Against N-Nitrosodiethylamine-Induced Hepatocarcinogenesis.

Qsee H S, Prasad Kisan Tambe, Sachin Shetty, Maya P Shetty, Anjali Singh, Komal Rana, Sanjay Bharati.

  Mitochondria-targeted antioxidants (MTAs) accumulate in mitochondria to mitigate mitochondrial oxidative stress. The present study investigates the anticancer therapeutic potential of two MTAs, MitoQ, and Mito-TEMPO, in rodent N-nitrosodiethylamine-induced hepatic cancer. Tumor-bearing male Wistar rats were treated with MitoQ (0.125 mg/kg b.w. orally), Mito-TEMPO (0.100 mg/kg b.w. intraperitoneally), or their combination for 6 weeks. The therapeutic effects of these MTAs were assessed in terms of total tumor number, multiplicity, and dielectric properties. Inflammatory level, DNA damage, apoptotic, and cell proliferation markers were assessed using ELISA and immunohistochemistry. Mitochondrial oxidative stress, activities of mitochondrial antioxidant enzymes, and electron transport chain enzymes were assessed using biochemical methods. Results revealed a significant (p ≤ 0.05) reduction in total number of tumors and tumor multiplicity, improved mitochondrial antioxidant system, electron transport, membrane potential and a significant (p ≤ 0.05) decrease in mitochondrial LPO and mitochondrial ROS when compared to untreated Tumor group. Furthermore, treatment significantly (p ≤ 0.05) modulated the levels of IL-6, TNF-α, 8-OHdG, bax, caspase-3, PCNA, Ki67, connexin, and cadherin proteins in tumors. In conclusion, both MitoQ and Mito-TEMPO have appreciable anticancer therapeutic potential against N-nitrosodiethylamine-induced hepatic cancer. The combination treatment of these two MTAs also exhibited additive anticancer therapeutic potential on tumor profile. Therefore, MTA-based anticancer therapy approach holds a promising future.

Keywords:  Mito‐TEMPO; hepatocellular carcinoma; mitochondria‐targeted antioxidants; mitoquinone

DOI:  https://doi.org/10.1002/cbf.70245
Rejuvenation Res. 2026 Jun 17. 15491684261460844

Fucoxanthin Promotes Longevity and Neuroprotection in Caenorhabditis elegans via DAF-16 and Autophagy Pathways.

Seona Kim, Sang-Kyu Park.

  Identification of natural compounds that delay aging and prevent age-related neurodegeneration is a key goal in gerontology. Fucoxanthin, a marine-derived xanthophyll, exhibits potent antioxidant properties, yet its effects on organismal aging and specific molecular mechanisms remain underexplored. Here, we investigated the pro-longevity and neuroprotective effects of fucoxanthin using Caenorhabditis elegans. Fucoxanthin supplementation significantly extended the mean lifespan of wild-type nematodes by 12.1% and improved health span, as evidenced by delayed age-related motility decline and enhanced resistance to oxidative stress. Notably, this lifespan extension occurred without compromising reproductive fitness. Genetic analysis revealed that the beneficial effects of fucoxanthin require the FOXO transcription factor DAF-16 and the autophagy-essential gene bec-1. Furthermore, fucoxanthin treatment increased autophagic flux and upregulated the expression of SKN-1/Nrf2-dependent detoxification genes, hsp-16.2 and gst-4. In nematode models of Alzheimer's and Parkinson's disease, fucoxanthin significantly ameliorated Aβ-induced paralysis and protected against dopaminergic neurodegeneration and α-synuclein accumulation in a DAF-16-dependent manner. Collectively, our findings demonstrate that fucoxanthin acts as a multitarget geroprotector that promotes healthy aging through the coordinated activation of DAF-16 and autophagy, suggesting its potential as a therapeutic intervention for age-related decline.

Keywords:  Caenorhabditis elegans; DAF-16; aging; autophagy; fucoxanthin; neuroprotection

DOI:  https://doi.org/10.1177/15491684261460844
Physiol Behav. 2026 Jun 18. pii: S0031-9384(26)00211-8. [Epub ahead of print] 115427

Mitochondrial remodeling in obesity: mechanistic links to impaired energy metabolism and therapeutic perspectives.

Welington Henrique Justo Neto, Camila de Oliveira Ramos, Claudio Teodoro De Souza.

  Obesity is characterized not only by excessive adiposity but also by profound disturbances in cellular and systemic energy homeostasis. Metabolic inflexibility, defined as the impaired ability to adapt substrate utilization in response to nutrient availability and energetic demands, has emerged as a central feature of obesity-associated metabolic dysfunction. Increasing evidence suggests that mitochondrial remodeling represents an important mechanism linking obesity to tissue-specific metabolic alterations, systemic metabolic dysfunction, and insulin resistance. Across adipose tissue, skeletal muscle, and liver, obesity induces tissue-specific alterations in mitochondrial biogenesis, dynamics, oxidative metabolism, quality-control pathways, and redox signaling, ultimately disrupting substrate utilization and insulin signaling. Importantly, mitochondrial adaptations appear highly dynamic and context dependent, suggesting that certain responses may initially arise as compensatory mechanisms before becoming maladaptive during disease progression. In addition, translational differences between experimental models and humans contribute to the heterogeneity observed in obesity-associated mitochondrial phenotypes. Here, we integrate preclinical and clinical evidence to examine the molecular mechanisms underlying tissue-specific mitochondrial remodeling and its contribution to metabolic inflexibility. We further discuss how lifestyle, pharmacological, and surgical interventions modulate mitochondrial pathways involved in restoring metabolic flexibility and improving metabolic health. Collectively, this review highlights tissue-specific mitochondrial remodeling as a dynamic and context-dependent process linking obesity to metabolic inflexibility and impaired metabolic adaptability, while identifying mitochondrial plasticity as a promising therapeutic target.

Keywords:  Adipose Tissue; Energy Metabolism; Insulin Resistance; Mitochondria; Muscle, Skeletal; Obesity

DOI:  https://doi.org/10.1016/j.physbeh.2026.115427
Eur Geriatr Med. 2026 Jun 16.

Mealtime irregularity is associated with higher serum growth differentiation factor-15 levels in older adults: the explanatory role of dietary quality.

Kaori Kinoshita, Yosuke Osuka, Georg von Fingerhut, Kazuhiro Yoshiura, Noriko Hori, Shosuke Satake, Shigenobu Shibata, Hidenori Arai.

   PURPOSE: This study examined the association between mealtime irregularity and Growth Differentiation Factor-15 (GDF-15)-a potential biomarker of biological aging-and evaluated whether this association could be explained by poor dietary quality among community-dwelling older adults.
METHODS: This cross-sectional study analyzed data from 378 disability-free adults aged ≥ 65 years from the Higashiura Study. Eating habits (regular vs. irregular) were assessed during the interviews. Dietary quality was evaluated using nutrient density scores from the Nutrient-Rich Food Index, calculated from 3-day dietary records. The association among mealtime irregularity, dietary quality, and serum GDF-15 levels was examined using mediation analysis after adjusting for age, sex, comorbidities, sleep duration, physical activity, smoking status, employment status, and total energy intake.
RESULTS: Participants with irregular mealtimes were significantly younger than those with regular mealtimes (mean ± standard deviation: 73.3 ± 4.6 vs. 75.1 ± 5.6 years, p = 0.014) and had higher serum GDF-15 levels (least-squares means, 95% confidence interval [CI]: 1161.4, 1063.4-1270.2 vs. 1028.0, 988.4-1068.9 pg/mL, p = 0.009). In the mediation analysis, lower nutrient density partially explained the association between mealtime irregularity and higher GDF-15 levels (β, 95% CI: total effect: 0.053, 0.0078-0.0977; direct effect: 0.046, 0.0004-0.0898; indirect effect: 0.008, 0.0001-0.0205; mediation proportion: 14.5%).
CONCLUSION: Although participants with irregular mealtimes were significantly younger than those with regular mealtimes, they showed higher levels of biological aging markers. Dietary quality partially accounted for this association. These findings suggest that dietary quality may be an important consideration for older adults with irregular mealtimes.

Keywords:  Biological aging; Chronononutrition; Dietary quality; Mealtime irregularity; Mediation analysis; Older adults

DOI:  https://doi.org/10.1007/s41999-026-01524-9
ACS Omega. 2026 Jun 09. 11(22): 32777-32789

Antiaging Effects of Mannose-6-Phosphate through Enhanced Mitochondrial Function and Collagen Remodeling.

Muniba Munir, Mengxin Zhang, Shahin Shah Khan, Lin Wu, Jun Wei, Hao Yin, Qi Zhou, Yian Zeng, Peng Shu, Luo Liu.

Aging is closely linked to mitochondrial dysfunction and the deterioration of the extracellular matrix (ECM), especially collagen. Mannose-6-phosphate (M6P), a naturally occurring glycolytic intermediate, has gained attention as a bioactive compound with potential antiaging benefits, modulating cellular metabolism. This study investigates the role of M6P in mitochondrial activity, oxidative stress, autophagy, and collagen remodeling. In vitro experiments with human keratinocytes and dermal fibroblasts revealed that M6P treatment significantly increased ATP, NADH, and NAD+ levels, thereby enhancing mitochondrial function and reversing UV-induced mitochondrial damage. Additionally, M6P promoted mitophagy and reduced the level of intracellular oxidative stress by 82%, indicating its antioxidant properties. Transcriptomic analysis showed that M6P up-regulated genes are involved in collagen synthesis and DNA repair, contributing to cellular defense against UV damage. Furthermore, a clinical trial was conducted at Zhejiang Xiaoshan Hospital with 36 healthy female participants over 56 days to test the effect, which further confirmed the improvements in skin firmness, elasticity, and wrinkle reduction following the use of the M6P antiaging cream. Overall, M6P appeared as a promising candidate for antiaging, which supports mitochondrial health, reduces oxidative damage, and promotes collagen regeneration.

DOI: https://doi.org/10.1021/acsomega.6c01710
Pharmacol Res. 2026 Jun 15. pii: S1043-6618(26)00216-1. [Epub ahead of print]230 108301

Ketone metabolism at the interface of atherosclerosis and brain dysfunction.

Young-Kook Kim, Juhyun Song.

  Atherosclerosis and brain dysfunction converge through vascular inflammation, endothelial injury, and regional bioenergetic failure of the neurovascular unit. Ketone bodies, including acetoacetate and D-β-hydroxybutyrate, perform critical roles in metabolic signaling by serving as alternative oxidative substrates for ATP production and bioactive signaling molecules that modulate cellular pathways. In the arterial wall, ketones improve endothelial function, reduce inflammation, and shift macrophages away from proinflammatory states, as well as induce changes that are predicted to limit lesion growth and enhance plaque stability. In the brain, ketone bodies serve as alternative energy substrates under conditions of hypoperfusion or impaired glucose metabolism, while also improving synaptic resilience through mitochondrial and epigenetic mechanisms. By coupling vascular inflammation with cerebral energetics via convergent immunometabolism pathways, ketone metabolism has emerged as a versatile therapeutic target. Nonetheless, effective clinical translation will require individualized strategies that account for metabolic and genetic variability, thereby positioning personalized ketone-based interventions as a promising avenue at the critical intersection of cardiovascular disease and neurodegeneration. Thus, this review aims to summarize the evidence on metabolic alterations spanning hepatic ketogenesis to cellular utilization, highlighting the implications of these alterations for vascular function and brain function.

Keywords:  Acetoacetate; Atherosclerosis; Brain dysfunction; Ketogenic diet; Ketone body; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.phrs.2026.108301
Food Funct. 2026 Jun 01.

Oleuropein and hydroxytyrosol enhance mitochondrial function and biogenesis in SH-SY5Y cells through estrogen-like mechanisms.

Manuela Leri, Daniele Nosi, Diletta Ami, Federica Bovio, Matilde Forcella, Federica Carnemolla, Paolo Mereghetti, Paola Fusi, Antonino Natalello, Massimo Stefani, Niccolò Taddei, Monica Bucciantini.

Age-related hormonal and metabolic changes critically increase vulnerability of neurons to neurodegeneration and cognitive decline. Estrogens are known to support neuronal survival, synaptic plasticity, and mitochondrial function, yet hormone replacement therapies have shown inconsistent neuroprotective outcomes. Safe alternatives are therefore highly desirable. In this study, we characterize Oleuropein aglycone (OleA) and hydroxytyrosol (HT), two of the main bioactive phenolic compounds found in extra virgin olive oil (EVOO), as multitarget neuromodulators with estrogen-like and neuroprotective potential. Unlike most studies on phytoestrogens, which have focused on single pathways such as estrogen receptor activation, our findings reveal a broader spectrum of actions. OleA and HT simultaneously modulate ERβ and IGF1R signaling, regulate Ca2+ dynamics through ryanodine, AMPA, and NMDA receptors, remodel the neuronal lipidome, and promote mitochondrial biogenesis and metabolic efficiency. Moreover, they influence amyloid-binding alcohol dehydrogenase (ABAD) expression, a mitochondrial target implicated in Alzheimer's disease. By converging on receptor signaling, lipid metabolism, and mitochondrial function, these compounds provide a systems-level perspective on neuronal protection. This multitarget activity, which mimics estrogen-like signaling, positions the investigated EVOO-derived phenolic compounds as safe dietary agents to counteract the neuronal decline associated with estrogen loss during ageing.

DOI: https://doi.org/10.1039/d6fo00178e
Food Funct. 2026 Jun 15.

Taurine supplementation at the crossroads of metabolism, inflammation and aging: mechanistic and nutritional perspectives.

Benedikt Justus Beine, Melissa Castellano, Jarlei Fiamoncini, Karsten Hiller.

Taurine is a non-proteinogenic β-amino acid that plays fundamental roles in cellular homeostasis. Although it is the most abundant free amino acid in many tissues, the full spectrum of its molecular functions has only recently begun to be elucidated. Taurine supplementation has shown promising outcomes in human studies, with emerging relevance in precision nutrition and the prevention of metabolic and age-related diseases. In this review, we summarize the current knowledge on taurine's molecular mechanisms, including its roles in antioxidant defense, anti-inflammatory signaling, calcium regulation, mitochondrial function, and lipid metabolism. We integrate mechanistic insights with evidence from clinical and nutritional studies examining taurine supplementation in the contexts of oxidative stress, inflammation, metabolic syndrome, and physical performance. Increasing data suggest that taurine can modulate key pathways linked to metabolism, inflammation, and healthy aging. Physiological synthesis and dietary intake appear sufficient to maintain basal health; however, human trials indicate that supplementation of 1-6 g day-1 may further promote metabolic resilience and mitochondrial function without adverse effects. Collectively, these findings position taurine as a promising dietary compound at the interface of metabolism, inflammation, and aging, highlighting its potential as a modulator of healthspan within precision nutrition strategies.

DOI: https://doi.org/10.1039/d6fo01808d
Physiol Rep. 2026 Jun;14(12): e70982

Age-related arterial stiffness and cerebrovascular dysfunction in mice correlate with cognitive impairment but are not reduced with long-term ALT-711 treatment.

Emily H Reeve, Abigail E Cullen, Skylyn J Ferguson, Maxwell Braker, Ainsley P Hogan, Alexandra Famiano, Ashley E Walker.

  Age-related increases in large artery stiffness contribute to cerebrovascular dysfunction and cognitive impairment. Alagebrium Chloride (ALT-711) is a collagen crosslink breaker that reduces vascular stiffness. We hypothesized that long-term treatment with ALT-711 would reverse age-related large artery stiffness, thereby preserving cerebral artery function and cognitive function. We treated old male and female C57BL/6 mice (20 months) with ALT-711 (1 mg/kg/day) or vehicle via oral gavage for 4 months and measured arterial stiffness, cerebral artery endothelial function, cognitive function, and collagen crosslinking. Treatment with ALT-711 did not significantly reduce stiffness in large arteries or cerebral arteries. There was no effect of ALT-711 on cerebral artery endothelial function, cognitive function, or collagen crosslinking. However, we found that collagen crosslinking was greater in old mice than in young, untreated C57BL/6 mice. In old mice, aortic collagen crosslinking was correlated with carotid artery passive stiffness. Additionally, among old mice, the passive stiffness of the cerebral artery negatively correlated with cerebral artery endothelial function and cognitive function. Cerebral artery endothelial function was negatively correlated with Frailty Index. In sum, age-related cerebral artery stiffness is negatively correlated with cognitive function and may be a promising therapeutic target to combat cerebrovascular dysfunction and cognitive decline with age.

Keywords:  Alagebrium chloride; aging; arterial stiffness; collagen crosslinking; endothelial dysfunction

DOI:  https://doi.org/10.14814/phy2.70982
J Int Soc Sports Nutr. 2026 Dec 31. 23(1): 2679716

Effects of carnosine supplementation on physical endurance: a placebo-controlled randomized clinical trial.

Timothy E O'Toole, Christopher J Wingard, Sonja K Bariess, Catherine E Crandell, Alok R Amraotkar, Hong Gao, Aruni Bhatnagar.

   BACKGROUND: Carnosine (β-alanine-L-histidine) is an endogenous dipeptide found in abundance in highly metabolic tissues such as skeletal muscle and the brain, where it is thought to play a role in intracellular buffering, and thereby, promote anaerobic glycolysis. Due to its perceived ability to support muscle energetics, carnosine, and its precursor, β-alanine, have found widespread use as performance-enhancing supplements. Nevertheless, the utility and efficacy of carnosine in enhancing physical performance have not been rigorously evaluated.
METHODS: We conducted a placebo-controlled clinical trial in which 299 participants were randomized to consume either placebo or carnosine-containing capsules (2 g per day). Several assessments of physical performance (hand grip strength, bilateral calf raise, 2-min step test, gait speed) were measured before initiating supplementation (Baseline: Visit-2) and after approximately 6 week (Visit-3) and 12 week (Visit-4) of supplementation. At each clinical visit, blood and urine were also collected. For Visit-3 and Visit-4, absolute changes and percent changes from baseline were calculated for each physical function measurement.
RESULTS: At Visit-3 we observed a statistically significant (p = 0.018) increase in the calf raise measure (number of bi-lateral flexions to exhaustion) for those in the carnosine supplementation group younger than 40 years of age. At Visit-4 we observed a statistically significant (p = 0.010) increase in the number of steps for males in the carnosine supplementation group greater than 40 years age and a trend toward significance (p = 0.06) for all males taking carnosine. No significant (p < 0.05) differences were observed in the carnosine versus placebo supplementation groups for any other physical performance measure.
CONCLUSIONS: In select age groups, carnosine supplementation improves muscular and cardiorespiratory endurance but not grip strength. The benefits appeared to be limited to males. Carnosine supplementation is likely to have beneficial effects in those undertaking short-term repetitive movements.

Keywords:  Carnosine; clinical trial; endurance; physical performance

DOI:  https://doi.org/10.1080/15502783.2026.2679716
J Appl Physiol (1985). 2026 Jun 18.

Beneficial vascular effects of oral phosphatidylserine supplementation in type 2 diabetes.

Neil J McMillan, Marc A Augenreich, Francisco I Ramirez-Perez, Gavin Power, Katherine Burr, Olubodun M Lateef, Nagarajan Manikandan, Christopher A Foote, Natnicha Imkaew, Thomas J Jurrissen, Yoskaly Lazo-Fernandez, Edgar E Betancourt-Cortes, Larissa Ferreira-Santos, Jesus H Beltran-Ornelas, Camila Manrique-Acevedo, Luis A Martinez-Lemus, Jaume Padilla.

  Endothelial insulin resistance is a characteristic of type 2 diabetes (T2D) that contributes to reduced nitric oxide bioavailability, impaired vasodilation, and arterial stiffening. We recently provided evidence that endothelial insulin resistance in T2D may be attributed to the shedding of insulin receptors by ADAM17. As prior work by others suggested that exogenous phosphatidylserine (PS) can competitively inhibit ADAM17, we hypothesized that oral PS supplementation would improve vascular function in diabetes. First, we corroborated the ability of PS to interact with and inhibit ADAM17 activity using in vitro approaches and experiments in isolated arteries. Next, we tested the vascular effects of PS in diabetic mice (db/db) and subsequently in individuals with T2D through a randomized, double-blind, placebo-controlled clinical trial. In a cell-free system, we found soluble PS binds to ADAM17 and blunts its activity, an effect also observed in cultured endothelial cells and isolated arteries, underscoring its inhibitory capacity. In diabetic mice, oral administration of PS (200mg/kg/day for 4wk) improved insulin-induced dilation in isolated resistance arteries and reduced ex vivo and in vivo indices of arterial stiffness. In individuals with T2D, PS supplementation (900mg/day for 4wk, delivering ~280mg/day PS) enhanced leg blood flow responses to an oral glucose load and reduced load-dependent aortic pulse wave velocity. Lastly, we observed that PS reduced vascular oxidative stress. This work supports the potential of oral PS as a therapeutic strategy to improve vascular function in T2D, and suggests that the beneficial effects of PS may be driven by its vascular insulin-sensitizing and antioxidant actions.

Keywords:  diabetes; phosphatidylserine; vascular function

DOI:  https://doi.org/10.1152/japplphysiol.00281.2026
Brain Res. 2026 Jun 17. pii: S0006-8993(26)00292-1. [Epub ahead of print] 150432

cGAS-STING signaling pathway: a central pathological mechanism and emerging therapeutic target for postoperative cognitive dysfunction.

Xiaoqin Wu, Baolin Zhong, Yongxing Xu, Yinsiqing Lai, Xinming Wen.

  Postoperative cognitive dysfunction (POCD) is a prevalent neurological complication in older patients following surgery. However, the upstream molecular triggers of perioperative neuroinflammation, a key factor in its pathogenesis, remain insufficiently understood. This review systematically examines the emerging evidence implicating the cGAS-STING signaling pathway as a potentially central mediator in the pathological progression of POCD. Integrating recent advancements, we outline a critical pathological cascade in POCD: perioperative stressors, including anesthesia and surgical trauma, induce mitochondrial injury, resulting in the release of mitochondrial DNA (mtDNA) into the cytosol. This leaked mtDNA functions as an endogenous danger signal, activating the cGAS-STING pathway in brain microglia. Activation of this pathway drives neuroinflammation, characterized by proinflammatory (M1-like) microglial polarization, regulated cell death (e.g., pyroptosis), and a self-perpetuating cycle of mitochondrial dysfunction, ultimately leading to neuronal damage and cognitive decline. We propose the mtDNA-cGAS-STING axis as a candidate pivotal link between perioperative stress and the neuropathology of POCD, based on converging preclinical evidence. Therapeutic strategies targeting this pathway, such as cGAS-STING inhibition or the promotion of mitophagy, have shown significant neuroprotective effects in preclinical studies. These findings offer promising avenues for the prevention and treatment of POCD and highlight potential implications for perioperative neuroprotection in older adults.

Keywords:  Microglia; Mitochondrial DNA; Neuroinflammation; Postoperative cognitive dysfunction; cGAS-STINGsignaling pathway

DOI:  https://doi.org/10.1016/j.brainres.2026.150432
Front Genet. 2026 ;17 1836446

Turning back time: a comprehensive list of interventions that decrease next-generation epigenetic aging clocks in humans.

Adiv A Johnson, David A Sinclair.

  Epigenetic aging clocks estimate age from DNA methylation patterns and have become central tools in longevity research. More recently, next-generation clocks have been developed to better compensate for the known divergence between chronological age and epigenetic age in ways that relate to lifestyle, health, and age-related disease. Although epigenetic clocks represent investigational biomarkers, these newer models are more strongly associated with all-cause mortality risk than first-generation clocks. As such, interventions that modify them are of interest. To test this, we performed a series of systematic searches and identified 41 human studies reporting the effects of interventions on at least one next-generation epigenetic clock. Our data suggest that a diverse range of pharmaceutical, lifestyle, supplementation, non-pharmaceutical clinical, and psychosocial interventions can decrease epigenetic age, including exercise, a plant-rich diet, the GLP-1 receptor agonist semaglutide, caloric restriction, ketamine, omega-3 fatty acids, a multivitamin-multimineral supplement, umbilical cord plasma, and the cholesterol-lowering drug pitavastatin. Nicotinamide riboside, rapamycin, senolytics, and several other interventions showed no detectable effect, whereas plasmapheresis and other therapeutics accelerated epigenetic aging. We also summarize reported effect sizes and compare next-generation clocks with respect to their frequency of use and responsiveness to intervention.

Keywords:  aging biomarker; biohorology; clinical trials; epigenetic age reversal; epigenetic aging clock; next-generation clock

DOI:  https://doi.org/10.3389/fgene.2026.1836446
Aging Cell. 2026 Jun;25(6): e70594

Aging Impairs Macrophage Phagocytosis Through Mitochondrial ROS-Induced Collagen Production.

Yuming Wang, Xin Xu, Nuanqin Shen, Ping Han, Liuyi Wu, Yi Jin, Yiming Sun, Lanlan Xiao, Jinyou Li, Lan Wang, Yunmei Yang, Qin Zhang, Weiqian Chen, Chaohui Yu, Bowen Wu.

Macrophages are pivotal immune cells due to their phagocytic capabilities, yet the impact of aging on macrophage phagocytosis remains poorly understood. Using comprehensive in vitro and in vivo phagocytic assays, we demonstrate significantly reduced phagocytic activity in monocyte-derived macrophages from aged humans and mice compared to young counterparts. RNA-seq analysis revealed upregulated expression of extracellular matrix protein genes, particularly collagens, in aged macrophages; manipulation of COL1A1 expression can significantly affect phagocytosis. Protein interaction assay identified binding between collagen and actin filaments, which inhibits F-actin turnover and consequently impairs phagocytic function. Also, we found that mitochondrial ROS is the driving force of collagen overproduction and MitoTEMPO rejuvenates macrophage phagocytosis via restoring actin dynamics. In a mouse model, MitoTEMPO significantly boosted the phagocytosis of peritoneal macrophages against bacteria. These findings highlight the fundamental role of mitochondrial redox balance and collagen production in controlling macrophage phagocytic function, identifying them as targetable mechanisms for promoting healthy immune aging.

DOI: https://doi.org/10.1111/acel.70594
J Endocrinol. 2026 Jun 17. pii: JOE-25-0381. [Epub ahead of print]

Probiotic Lactobacillus Reuteri KUB-AC5 Provides Cardioprotection via Mitigating Cardiac Mitochondrial Dysfunction in Obese Rats.

Chanisa Thonusin, Titikorn Chunchai, Parameth Thiennimitr, Chayodom Maneechote, Chanon Kunasol, Jirapas Sripetchwandee, Siriporn C Chattipakorn, Nipon Chattipakorn.

  Cardiac mitochondrial dysfunction is a crucial mechanism underlying obesity-induced cardiovascular diseases. A close link between obesity and gut microbiota has been revealed, and the benefits of gut microbiota modulation by probiotics have been widely identified. Although the probiotic Lactobacillus reuteri KUB-AC5 exerted anti-inflammatory activity and enhanced the activity of beneficial microbes, the effects of this probiotic on mitochondria in the obese heart have never been investigated. Male Wistar rats were divided into 4 groups to receive either a normal diet (ND; n = 9) or a high-fat and high-calorie diet (HFCD; n = 30) for 24 weeks. At the beginning of week 13, ND-fed rats received vehicle, while HFCD-fed rats were further subdivided into 3 groups (n = 10/group) to receive either vehicle, a live probiotic Lactobacillus reuteri KUB-AC5, or a heat-killed probiotic Lactobacillus reuteri KUB-AC5. At the end of week 24, cardiac functions were evaluated. The rats were then euthanized to enable blood and cardiac ventricle collection. Evidence from the obese rats treated with Lactobacillus reuteri KUB-AC5 in both forms indicated reduced body weight and attenuated insulin resistance. Regarding the heart, obese rats treated with either form of Lactobacillus reuteri KUB-AC5 had improved cardiac functions, mitochondrial dynamics, mitochondrial biogenesis, fat and ketone body utilization, anaplerosis, ATP production, and oxidative phosphorylation. In addition, treatment with this probiotic diminished oxidative stress and restored antioxidative capacity of cardiac mitochondria. Our preclinical findings in male rats highlighted the benefits of the probiotic Lactobacillus reuteri KUB-AC5, given in both live and heat-killed forms, in alleviating obesity-induced cardiac mitochondrial dysfunction.

Keywords:  Cardiovascular disease; Heart; Lactobacillus reuteri KUB-AC5; Mitochondria; Obesity

DOI:  https://doi.org/10.1530/JOE-25-0381
Exp Physiol. 2026 Jun 19.

Mitochondrial peptide MOTS-c suppresses systemic and cardiac inflammasome activation in a diabetic rat model.

Aimee R Mills, Antonio de Souza, Toan Pham, Odunayo O Mugisho.

  Type 2 diabetes mellitus (T2DM) is associated with chronic systemic and cardiac inflammation, contributing to the development of diabetic cardiomyopathy. The mitochondrial-derived peptide mitochondrial open reading frame of the 12S rRNA type-C (MOTS-c) has emerged as a promising regulator of metabolic and inflammatory pathways. In this study, we investigated the effects of MOTS-c treatment on leucine-rich repeat and pyrin domain-containing receptor 3 (NLRP3) inflammasome activity in a high-fat diet and streptozotocin-induced T2DM rat model. MOTS-c treatment significantly reduced fasting blood glucose and circulating C-reactive protein levels, while selectively modulating plasma inflammatory cytokines, including interleukin (IL)-10 and IL-1β. Immunohistochemical analysis revealed reduced levels of NLRP3, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), and cleaved caspase-1 in left ventricular tissue following MOTS-c administration. Correlation analyses linked IL-18 and IL-1β with elevated markers, including low-density lipoprotein and uric acid, suggesting interplay between overall health and inflammasome activity. These results indicate that MOTS-c modulates both systemic and cardiac inflammation in T2DM, providing a novel therapeutic approach for reducing cardiovascular risk in diabetic patients.

Keywords:  MOTS‐c; diabetic heart; inflammasome; inflammation

DOI:  https://doi.org/10.1113/EP093714
Neuropharmacology. 2026 Jun 19. pii: S0028-3908(26)00256-X. [Epub ahead of print] 111082

Repurposing citicoline for single prolonged stress-induced behavioral and hippocampal molecular abnormalities in male mice: novel mechanistic attenuation of endoplasmic reticulum stress, mitochondrial dysfunction, oxidative stress, and apoptosis.

Nehal G Fahmy, Nada M Kamel, Shireen A Hedya, Aya M Abd El-Latif.

  Post-traumatic stress disorder (PTSD) is a debilitating psychiatric disorder with limited effective pharmacological options. Endoplasmic reticulum (ER) stress and mitochondrial dysfunction have emerged as pivotal pathological mechanisms in PTSD pathophysiology, yet therapies targeting these pathways remain largely unexplored. Citicoline, recognized for its neuroprotective properties and capacity to modulate mitochondrial homeostasis, presents a promising candidate for intervention. This study investigated citicoline's therapeutic efficacy against behavioral and hippocampal molecular abnormalities induced by single prolonged stress (SPS) in male mice. Thirty-six mice were subdivided into control, citicoline (Citi) (100 mg/kg, p.o for 7 days), SPS (2-hour restraint, 20-minute forced swim, ether exposure), and SPS+Citi (SPS followed by citicoline for 7 days) groups. Citicoline administration effectively reversed stress-induced behavioral impairments in social novelty preference, marble burying, and cue-induced freezing. At the molecular level, citicoline restored ER homeostasis by attenuating the toxic unfolded protein response characterized by reductions in phosphorylated protein kinase RNA-like ER kinase, activating transcription factor (ATF) 4, and ATF6 while upregulating the protective X-box binding protein 1. Such improvements were accompanied by reactivation of impaired mitophagy through enhanced PTEN-induced kinase 1 and parkin expression, facilitating clearance of damaged mitochondria and reactive oxygen species. Furthermore, citicoline effectively countered oxidative stress, evidenced by suppressing malondialdehyde-mediated lipid peroxidation while restoring glutathione antioxidant reserves. Citicoline also normalized mitochondrial biogenesis by upregulating peroxisome proliferator-activated receptor gamma coactivator 1-alpha and prevented neuronal apoptosis by suppressing caspase-3. Collectively, these findings establish citicoline as a promising multi-targeted therapeutic candidate for behavioral and hippocampal molecular abnormalities after SPS in male mice.

Keywords:  ER stress; PTSD; SPS; apoptosis; citicoline; mitophagy

DOI:  https://doi.org/10.1016/j.neuropharm.2026.111082
Circ Heart Fail. 2026 Jun 15. e014397

Targeting Mitochondrial Dysfunction With Elamipretide (SS-31) Improves Skeletal Muscle Performance in a HFpEF Rat Model.

Beatrice Vahle, Sven Weidner, André Tomalka, Antje Schauer, Antje Augstein, Anita Männel, Peggy Barthel, Janet Friedrich, Grietje Beck, Siegfried Labeit, T Scott Bowen, Tobias Siebert, Axel Linke, Volker Adams.

   BACKGROUND: Exercise intolerance, promoted by skeletal muscle- and mitochondrial dysfunction, has been identified as a therapeutic target in heart failure with preserved ejection fraction (HFpEF). In the context of mitochondrial dysfunction, altered cardiolipin integrity has been reported in the myocardium of HFpEF, suggesting Elamipretide, a cardiolipin stabilizing agent, as potential therapeutic approach. The present study investigated cardiolipin dysregulation in the skeletal muscle of HFpEF rats and analyzed the effect of Elamipretide treatment.
METHODS: Female zucker fatty spontaneously hypertensive heart failure F1 hybrid lean (n=10, control) and obese rats (n=24, HFpEF) were included. At 20 weeks of age, HFpEF rats were randomized into 2 groups receiving NaCl (n=12) or Elamipretide (n=12) for 12 weeks. Skeletal muscle tissue was collected for whole-muscle force, single-fiber mechanics, mitochondrial respiration, histology and molecular analyses.
RESULTS: HFpEF rats exhibited reduced cardiolipin levels (-6.8%, P=0.007) and maturation (shown via tafazzin expression), contractile dysfunction, titin hyperphosphorylation, fiber atrophy and increased oxidative stress markers. Elamipretide improved whole muscle (soleus: +8.2%, P=0.041, extensor digitorum longus: +10.9%, P=0.016) and single-fiber (soleus: +173.2%, P<0.001, extensor digitorum longus: +66.0%, P=ns) contractile function and titin phosphorylation (soleus: -35.4%, P<0.001, extensor digitorum longus: -40.2%, P<0.001), while preventing atrophy development (soleus: +49%, P=0.001, extensor digitorum longus: +54.8%, P<0.001). Improved mitochondrial function, presumably through cardiolipin-mediated improvements in oxidative phosphorylation, could be associated with muscle force and cardiolipin integrity.
CONCLUSIONS: Our data highlight cardiolipin stabilization as a key modulator of mitochondrial and contractile function in HFpEF, identifying Elamipretide as a promising therapeutic approach for skeletal muscle dysfunction.

Keywords:  animals; heart failure; mitochondria; obesity; stroke volume

DOI:  https://doi.org/10.1161/CIRCHEARTFAILURE.126.014397
BMC Womens Health. 2026 Jun 17.

Oral L-ergothioneine supplementation in women with suboptimal ovarian reserve: a single-center, open-label, self-controlled pilot study of ovarian reserve markers, endocrine profiles, and reproductive aging-related symptoms.

Wei Liu, Cong Guo, Wei Ding, Juan Cao, Hongying Ju, Fengjuan Liu, Guohua Xiao.

   PURPOSE: To evaluate the efficacy and safety of oral L-ergothioneine (EGT) in improving ovarian reserve and clinical symptoms in women with suboptimal ovarian function. As a proof-of-concept study, we explored correlations between hormonal shifts and symptom amelioration.
METHODS: This single-center, open-label trial enrolled 40 women (aged 35-45 years) experiencing age-related reproductive decline (baseline AMH: 1.0-3.0 ng/mL) and menstrual disorders. Participants received oral EGT (120 mg/day) for three consecutive menstrual cycles. The primary outcome was the change in serum AMH. Secondary outcomes included sex hormones (FSH, E2), antral follicle count, and validated questionnaires (KI, PSQI, SF-36) and an exploratory Menstrual Symptom Score.
RESULTS: Thirty-six participants completed the intervention without product-related adverse events. EGT supplementation was associated with increases in core ovarian markers: mean AMH increased from 1.81 ± 0.72 to 2.46 ± 1.54 ng/mL (mean change + 0.65 ng/mL, 95% CI [0.14, 1.17], p = 0.018). Concurrently, basal FSH decreased (8.38 ± 2.83 to 7.05 ± 2.51 mIU/mL, mean change - 1.33, 95% CI [- 2.50, - 0.17]; p = 0.032, FDR-adjusted p = 0.048) and E2 increased (43.78 ± 18.87 to 63.46 ± 50.81 pg/mL; mean change + 19.69, 95% CI [3.99, 35.38]; p = 0.019, FDR-adjusted p = 0.048). Clinical assessments showed progressive reductions in KI (5.42 ± 3.66 to 1.90 ± 2.16, p < 0.0001) and PSQI scores (6.89 ± 1.82 to 5.50 ± 1.40, p < 0.0001), alongside improved menstrual and SF-36 scores (p < 0.001). Subgroup analysis stratified by baseline ovarian reserve showed a significant AMH increase in the low-reserve subgroup (p = 0.017) but not the high-reserve subgroup. Exploratory correlation analysis showed that ΔFSH was associated with improvements in sleep quality (ΔPSQI, r = 0.43, p < 0.05) and E2 increases (r = -0.46, p < 0.05), linking hormonal stabilization directly to systemic relief.
CONCLUSION: In this open-label, single-arm pilot study, oral EGT supplementation was associated with increases in serum AMH and favorable shifts in the basal FSH/E2 profile, alongside improvements in reproductive aging-related and sleep symptoms. Because the design lacks a control group, these changes cannot be attributed to EGT alone and may partly reflect natural variation, regression to the mean, or placebo effects. These hypothesis-generating findings warrant confirmation in adequately powered, placebo-controlled trials.
TRIAL REGISTRATION: ChiCTR2500104484; Prospectively registered on 2025-06-18.

Keywords:  Anti-Müllerian hormone (AMH); Clinical trial; L-Ergothioneine; Oxidative stress; Reproductive aging; Suboptimal ovarian reserve

DOI:  https://doi.org/10.1186/s12905-026-04604-x
Front Psychol. 2026 ;17 1823236

Chronological age is differentially associated with cognitive performance according to climacteric stage: evidence from a Bayesian multivariate analysis in Chilean women.

Jonathan Lühr-Henríquez, Matías Castillo-Aguilar, Rosa Jurado-Barba, Cinthya Velásquez Muñoz, Cristian Núñez-Espinosa.

   Background: Women traversing menopause experience neuropsychological changes affecting cognitive domains such as memory, attention, and processing speed. However, the relationship between chronological age and cognitive performance across different climacteric stages remains poorly understood, particularly in Latin American populations. The menopausal transition is increasingly recognized as a critical period for women's cognitive health, characterized by profound neuroendocrine changes that may influence trajectories of cognitive aging. Chronological age was associated with better cognitive performance in early menopause, whereas in advanced postmenopause it was associated with lower performance. This pattern may reflect stage-specific differences related to reproductive aging, particularly across different phases of the climacteric.
Objectives: To examine whether chronological age differentially modulates cognitive performance according to climacteric stage in Chilean women from the Magallanes Region.
Methods: Three hundred sixty women aged 50-81 years were recruited and classified by climacteric stage: early menopause (≤4 years since last menstrual period, n = 126), intermediate postmenopause (5-8 years, n = 123), and advanced postmenopause (>9 years, n = 111). Cognitive performance was assessed using the Addenbrooke's Cognitive Examination-Revised (ACE-R) and the Symbol Digit Modalities Test (SDMT). A Bayesian multivariate model with two-way interaction terms was fitted, simultaneously evaluating ACE-R and SDMT as response variables.
Results: More advanced climacteric stage was associated with lower ACE-R and SDMT scores. Although the main effect of age at assessment showed high uncertainty, a significant age × climacteric stage interaction revealed that the age-cognition slope differed by stage. Specifically, in early menopause, older age was associated with better cognitive performance, whereas in advanced postmenopause, older age was associated with lower cognitive performance.
Conclusion: The association between chronological age and cognitive performance differed according to climacteric stage in Chilean women. These findings challenge the traditional view of age as a uniformly negative correlate of cognition and may have implications for cognitive screening strategies during the menopausal transition.

Keywords:  ACE-R; Bayesian analysis; SDMT; age; climacteric stage; cognition; menopause

DOI:  https://doi.org/10.3389/fpsyg.2026.1823236