bims-mistre 2026-09-20 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–09–20
fifteen papers selected by
Ellen Siobhan Mitchell, MitoQ

Mitokines as bioenergetic stress signals in cardiovascular disease: mitochondrial communication, endocrine adaptation, and translational implications.
Aging in Spaceflight, Oxidative Stress, and Microbiome Dysbiosis: A Comprehensive Review.
The Sentinel Hormone GDF-15, Glucocorticoid Homeostasis and Adrenal Disorders.
Synaptic Mitochondrial Oxidative Stress Contributes to Individual Variability in Age-Related Cognitive Inflexibility in Mice.
Resveratrol engages SIRT1/AMPK networks to restore BDNF signaling, autophagy, and mitochondrial function in age-related cognitive decline: A geroscience perspective.
Perimenopause as a potential window of cardiometabolic remodeling in heart failure with preserved ejection fraction: a missed opportunity for prevention.
Growth differentiation factor-15 and body roundness index in relation to cardiometabolic risk in young adults with obesity.
mtDNA alterations in muscle progenitors determine myoblast differentiation and disrupt skeletal muscle architecture.
Cardiovascular and Metabolic Outcomes of Hormone Replacement Therapy in Women Aged 65 Years and Older: A Systematic Review of Randomized Clinical Trials.
Effects of six weeks of guanidinoacetic acid supplementation with and without creatine monohydrate on cognitive function and markers of health in healthy adults.
Effects of a Combined Vitamin D3 and Docosahexaenoic Acid Intervention on Cognitive Function and Blood Pyroptotic Biomarkers in Older Adults with Mild Cognitive Impairment: A 12-Month Randomized, Double-Blind, Placebo-Controlled Trial.
Synaptic mitochondrial dysfunction and Alzheimer's disease: from molecular mechanisms to therapeutic strategies.
Adiposity and Cognitive Performance in Older Men and Women from the Study of Muscle, Mobility and Aging (SOMMA).
Hydroxytyrosol as a Multitarget Neuroprotective Agent: Molecular Mechanisms, Pharmacokinetics and Therapeutic Potential in Neurodegenerative Diseases.
Effects of Nutritional Supplements on Inflammatory Biomarkers in Overweight and Obese Adults: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

J Bioenerg Biomembr. 2026 Sep 14. pii: 52. [Epub ahead of print]58(1):

Mitokines as bioenergetic stress signals in cardiovascular disease: mitochondrial communication, endocrine adaptation, and translational implications.

Gino A Kurian.

  Cardiovascular disease is strongly influenced by mitochondrial dysfunction, yet how mitochondrial stress is communicated beyond the affected cell to coordinate systemic responses remains incompletely understood. Mitokines are stress-responsive signaling factors that link mitochondrial perturbation to cellular and interorgan adaptation. These include nuclear-encoded proteins such as fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), as well as mitochondrial-derived peptides including Humanin and MOTS-c. This review critically examines mitokine regulation and signaling in the context of cardiovascular stress, with emphasis on mitochondrial unfolded protein response and integrated stress response pathways, receptor and downstream signaling mechanisms, and the functional divergence among major mitokines. Transient mitokine responses during physiological or metabolic challenge may support metabolic flexibility, cytoprotection, and stress adaptation, whereas persistent elevations of FGF21 and GDF15 in cardiovascular and cardiometabolic disease frequently accompany unresolved mitochondrial stress and adverse clinical phenotypes. Importantly, such associations do not establish that sustained mitokine signaling is itself maladaptive, and major mechanistic uncertainties remain, particularly for mitochondrial-derived peptides. We integrate these observations within a proposed "mitokine code" framework in which mitokine identity, relative patterns, temporal dynamics, and disease context may collectively provide information about mitochondrial stress and systemic adaptation. We further evaluate the potential and current limitations of mitokines as cardiovascular biomarkers and therapeutic targets. This framework positions mitokine signaling at the interface between mitochondrial dysfunction, systemic stress adaptation, and cardiovascular disease while identifying mechanistic and translational questions requiring prospective validation.

Keywords:  Cardiovascular disease; Integrated stress response; Mitochondrial stress signaling; Mitochondrial unfolded protein response; Mitochondrial-derived peptides; Mitokines

DOI:  https://doi.org/10.1007/s10863-026-10136-8
Int J Mol Sci. 2026 Aug 26. pii: 7644. [Epub ahead of print]27(17):

Aging in Spaceflight, Oxidative Stress, and Microbiome Dysbiosis: A Comprehensive Review.

Charles C Naney, Joseph L Graves, Scott H Harrison.

  The evolutionary theory of aging demonstrates that the force of natural selection declines with age in multicellular organisms. Two population genetic mechanisms are consistent with the evolutionary theory: mutation accumulation and antagonistic pleiotropy. These in turn account for the physiological, cellular, and molecular mechanisms associated with aging. Spaceflight provides an opportunity to examine how organisms physiologically acclimate to environmental conditions. Mitochondria and the gut microbiome are central regulators of host metabolism, redox homeostasis, immune function, and physiological resilience, and both are impacted by host adaptations and acclimations. Mitochondrial dysfunction and oxidative stress have consequently emerged as important candidate mechanisms linking biological aging and spaceflight-associated physiological change. This review examines evidence surrounding mitochondrial dysfunction, oxidative stress, and gut microbiome dysbiosis across humans, mice, and fruit flies under spaceflight and corresponding terrestrial control conditions. This review reports further on the progression of theory and recent evidence from spaceflight missions for how biomarker genes most associated with mutation accumulation and antagonistic pleiotropy appear to have a core role in natural aging and extreme physiological acclimation.

Keywords:  aging; microbiota; oxidative stress; spaceflight

DOI:  https://doi.org/10.3390/ijms27177644
Endocr Rev. 2026 Sep 16. pii: bnag035. [Epub ahead of print]

The Sentinel Hormone GDF-15, Glucocorticoid Homeostasis and Adrenal Disorders.

Ilaria Bonaventura, Isabel Weigand, Andrea M Isidori, Matthias Kroiss, Martin Reincke.

  Growth and differentiation factor 15 (GDF-15) is a stress-responsive hormone secreted by various cell types in response to cellular stress. To regulate ingestive behaviour, suppress food intake, and induce nausea and vomiting during cellular stress, GDF-15 signals via a brainstem-restricted receptor, GFRAL. Elevated circulating GDF-15 levels serve as a biomarker of cellular stress and are increased in a wide range of diseases. GDF-15 has recently been established as a causal factor in cancer cachexia and GDF15-GFRAL antagonism is being pursued as a therapeutic strategy. Recent studies have highlighted a dynamic interplay between GDF-15 and the hypothalamus-pituitary-adrenal (HPA) axis, suggesting that GDF-15 acts as a sentinel hormone in stress responses. Here, we review the canonical role of GDF-15 in stress-related conditions and its potential impact on circadian regulation and HPA axis dysregulation. The review explores the potential activation of the HPA axis by GDF-15 and discuss the hypothesis that downstream glucocorticoid signalling may contribute to some of the cardiovascular, metabolic, immune, and musculoskeletal changes reported for GDF-15. Additionally, the review discusses the potential role of GDF-15 in adrenal insufficiency and its treatment and in adrenocortical carcinoma. In summary, this review aims to elucidate the role of GDF-15 in glucocorticoid homeostasis and adrenal disease in the context of the stress response.

Keywords:  Cushing’s syndrome; GDF-15; adrenal insufficiency; cortisol; glucocorticoids; stress

DOI:  https://doi.org/10.1210/endrev/bnag035
Aging Cell. 2026 Sep;25(9): e70716

Synaptic Mitochondrial Oxidative Stress Contributes to Individual Variability in Age-Related Cognitive Inflexibility in Mice.

Rui Yamada, Hirotaka Nagai, Chisato Numa, Yunhui Zhu, Midori Nagai, Kohei Ota, Yusuke Kawashima, Nobuhiko Ohno, Tomoyuki Furuyashiki.

  Aging is associated with impairments in cognitive flexibility, a key executive function supported by the medial prefrontal cortex (mPFC), yet the biological mechanisms underlying individual variability in age-related decline remain poorly understood. Here we investigated behavioral, ultrastructural, and proteomic correlates of cognitive inflexibility in mice across aging. Using a touchscreen-based attentional set-shifting task, we observed substantial individual variability in cognitive inflexibility among aged C57BL/6J mice. Volume electron microscopy of the mPFC revealed age-related reductions in synaptic density, but these structural changes did not correlate with cognitive performance. Instead, the proportion of synapses containing presynaptic mitochondria was inversely associated with cognitive flexibility in aged mice. To identify molecular correlates, we performed proteomic profiling of mPFC whole tissue and synaptosome fractions. Proteins associated with individual variability in cognitive inflexibility were largely distinct from those associated with chronological aging. Notably, synaptosomal proteins negatively correlated with cognitive performance were strongly enriched for mitochondrial pathways, including oxidative phosphorylation, mitochondrial translation, and the tricarboxylic acid cycle. Consistent with these findings, the mitochondria-targeted antioxidant MitoQ improved attentional set-shifting performance in aged mice without affecting initial learning. Proteomic analyses revealed that MitoQ reduced the abundance of synaptosomal mitochondrial proteins, particularly those involved in mitochondrial apoptotic signaling. Together, these results suggest that synaptic mitochondrial oxidative stress in the mPFC contributes to individual vulnerability to cognitive inflexibility. Targeting synaptic mitochondrial oxidative stress may therefore represent a promising strategy to preserve executive function during aging.

Keywords:  cognitive aging; mice; mitochondria; oxidative stress; prefrontal cortex; synapse

DOI:  https://doi.org/10.1111/acel.70716
Prog Neuropsychopharmacol Biol Psychiatry. 2026 Sep 12. pii: S0278-5846(26)00323-4. [Epub ahead of print]150 111925

Resveratrol engages SIRT1/AMPK networks to restore BDNF signaling, autophagy, and mitochondrial function in age-related cognitive decline: A geroscience perspective.

Ahmed Salem Al-Dhahi, Hayder M Al-Kuraishy, Mohamed N Fawzy, Gaber El-Saber Batiha.

  Age-related cognitive decline and neurodegenerative disorders present significant challenges in neuropsychiatry, as current therapeutic strategies largely fail to adequately address the complexities of cerebral aging. Resveratrol, a natural polyphenol, has become a promising multi-target neuroprotective agent that can affect multiple important pathways that are involved in aging and neurodegeneration at the same time. This review consolidates evidence indicating that resveratrol, particularly through bioavailability-enhanced formulations, activates SIRT1, stimulates AMPK, inhibits mTORC1, restores autophagic flux, and promotes mitochondrial biogenesis at plasma concentrations (1-10 μmol/L) achievable in humans. Preclinically, resveratrol augments BDNF-TrkB-CREB signaling, facilitates hippocampal neurogenesis, diminishes amyloid-β and tau pathology, and alleviates neuroinflammation and glial senescence. In clinical research, resveratrol has been associated with enhanced cognitive function and hippocampal connectivity in certain trials, as well as reduced inflammatory and metabolic markers associated with brain aging, although findings remain inconsistent. Resveratrol has emerged as a potential multi-target neuroprotective agent for mitigating age-related cognitive decline, owing to its proven safety record and enhanced pharmacokinetic properties. We asserted that the accumulated evidence necessitates the initiation of extensive randomized controlled trials in middle-aged and elderly individuals to assess its efficacy in maintaining cognitive function, alleviating brain aging, and delaying the onset of neurodegenerative diseases.

Keywords:  Autophagy; BDNF; Cognitive aging; Neuroinflammation; Neuroprotection; Resveratrol; SIRT1; mTOR

DOI:  https://doi.org/10.1016/j.pnpbp.2026.111925
Front Cardiovasc Med. 2026 ;13 1948320

Perimenopause as a potential window of cardiometabolic remodeling in heart failure with preserved ejection fraction: a missed opportunity for prevention.

Faith Adedayo Adejumo, Oluwayimika Oluwatobi Obielodan, Fiyinfoluwa Adetoye, Nicholas Aderinto.

  Heart failure with preserved ejection fraction (HFpEF) disproportionately affects women and has emerged as one of the most prevalent forms of heart failure worldwide. Although the marked increase in HFpEF incidence after menopause is well recognized, the biological events that initiate disease development remain poorly defined. Most mechanistic and clinical investigations have focused on postmenopausal women or established HFpEF, leaving the menopausal transition comparatively underexplored despite growing evidence that it represents a period of accelerated cardiometabolic change. This review synthesizes current evidence on reproductive aging, cardiometabolic remodeling, and the pathophysiological mechanisms underlying HFpEF to examine whether perimenopause represents a critical window in the development of the female HFpEF phenotype. Evidence from longitudinal cohorts and mechanistic studies indicates that visceral and epicardial adiposity, insulin resistance, adverse lipid remodeling, systemic inflammation, endothelial dysfunction, coronary microvascular impairment, arterial stiffening, and early cardiac remodeling emerge or accelerate during the menopausal transition. These biological alterations closely parallel established mechanisms implicated in HFpEF pathogenesis. Building on prior clinical and experimental evidence identifying the menopausal transition as a period of cardiovascular remodeling and increasing cardiovascular risk, we develop a temporal framework for female HFpEF. This framework considers whether, in susceptible women, HFpEF-relevant biological changes may begin to accumulate during perimenopause, become progressively amplified after menopause, and ultimately contribute to clinically manifest disease. We further examine how reliance on binary reproductive classifications, recruitment of predominantly postmenopausal cohorts, and the limited integration of reproductive staging into cardiovascular research may have contributed to this early phase of disease remaining largely unrecognized. Reframing perimenopause as a critical period of cardiovascular remodeling shifts attention from treating established HFpEF to identifying opportunities for earlier prevention. Prospective longitudinal studies incorporating standardized reproductive staging, comprehensive cardiovascular phenotyping, and biomarker profiling are now needed to determine whether the menopausal transition represents the earliest identifiable window for preventing HFpEF in women.

Keywords:  cardiometabolic remodeling; coronary microvascular dysfunction (CMD); heart failure with preserved ejection fraction; menopausal transistion; perimenopause

DOI:  https://doi.org/10.3389/fcvm.2026.1948320
Endocrine. 2026 09 16. pii: 299. [Epub ahead of print]91(1):

Growth differentiation factor-15 and body roundness index in relation to cardiometabolic risk in young adults with obesity.

Omar Jasim Mohammed, Hassanain K Mehdi.

   PURPOSE: Cardiometabolic risk in young adults is often subclinical. This cross-sectional study evaluated Growth Differentiation Factor-15 (GDF-15) and Body Roundness Index (BRI) in relation to cardiometabolic risk in young adults.
METHODS: Ninety adults aged 18-35 years were classified into control, low-risk, and high-risk groups using predefined criteria. Anthropometric, glycemic, and lipid parameters, hs-CRP, GDF-15, leptin, and adiponectin were analyzed using ANCOVA, partial correlation, regression, and ROC analysis.
RESULTS: GDF-15 rose progressively across groups (control 337.7 ± 82.6, low-risk 865.8 ± 76.9, high-risk 1130.7 ± 79.2 pg/mL; p < 0.001). Leptin, the leptin-to-adiponectin ratio, and adiponectin were higher in both risk groups than controls (p < 0.001), with no difference between risk groups. GDF-15 showed high discriminatory ability for controls versus obese groups (AUC 0.939-0.954), reflecting phenotypic separation, but only modest discrimination between low-risk and high-risk groups (AUC = 0.677, 95% CI 0.535-0.819; p = 0.024), the clinically relevant comparison. In exploratory subgroup regression, adiponectin was associated with GDF-15 in low-risk (β = 0.465, p = 0.011) and high-risk groups (β = 0.551, p = 0.038). Combining GDF-15 with waist-to-hip ratio gave a numerically higher AUC (0.708), although the difference was not formally tested.
CONCLUSION: GDF-15 levels increased progressively across the study groups and remained significantly different across groups after adjustment for age. GDF-15 and adiponectin showed very high discrimination between obese participants and controls but only modest discrimination between risk groups. These exploratory, cross-sectional findings identify GDF-15 as a candidate biomarker of cardiometabolic risk in young adults, requiring confirmation in larger prospective cohorts.

Keywords:  Adipokines; Body roundness index; Cardiometabolic risk; GDF-15; Obesity; Visceral adiposity; Young adult

DOI:  https://doi.org/10.1007/s12020-026-04784-4
Cell Rep. 2026 Sep 11. pii: S2211-1247(26)01057-0. [Epub ahead of print]45(9): 117979

mtDNA alterations in muscle progenitors determine myoblast differentiation and disrupt skeletal muscle architecture.

Ayesha Sen, Olivier R Baris, Yulia Schaumkessel, Sebastian Kallabis, Claudie Gabillard-Lefort, Valerie Desquiret, Rudolf J Wiesner, David Pla-Martín.

  Mitochondrial DNA (mtDNA) damage has been linked to age-related tissue decline, yet its impact on muscle stem cells (MuSCs) integrity remains unclear. Here, we used a dominant-negative variant of the mitochondrial helicase Twinkle (p.K320E) to induce mtDNA instability in C2C12 and MuSCs, and examined myogenic differentiation. In C2C12, mtDNA alterations impaired respiratory complex assembly, increased reactive oxygen species, and disrupted differentiation. Proteomic analyses of differentiated C2C12 revealed extensive remodeling of the mitochondrial proteome. In vivo, during muscle regeneration, MuSCs expressing K320E generated fibers showing mitochondrial dysfunction and elevated oxidative stress. Furthermore, when mtDNA instability was induced during early postnatal stages, mtDNA alterations were progressively transmitted to mature myofibers, resulting in persistent fiber remodeling of the skeletal muscle. Together, these findings identify mtDNA instability in muscle progenitors as a driver of skeletal muscle remodeling and reveal that even modest levels of mtDNA alterations are sufficient to compromise skeletal muscle function.

Keywords:  CP: developmental biology; mitochondria; mtDNA; muscle differentiation; satellite cells; skeletal muscle

DOI:  https://doi.org/10.1016/j.celrep.2026.117979
Clin Pharmacol. 2026 ;18 581397

Cardiovascular and Metabolic Outcomes of Hormone Replacement Therapy in Women Aged 65 Years and Older: A Systematic Review of Randomized Clinical Trials.

Taraneh Mousavi, Md Fitrat Hossain, Fadia T Shaya, Wanda Hill, Stephen N Davis.

   Background: The cardiovascular, kidney, and metabolic effects of hormone replacement therapy (HRT) in postmenopausal women, particularly those who initiate treatment after age 65, remain incompletely characterized. The objective of this systematic review was to evaluate evidence on these outcomes, with a focus on women aged 65 years and older.
Methods: PubMed, Embase, Scopus, and the Cochrane Library were searched for studies published between January 1, 2021, and February 28, 2026. Eligible studies included randomized controlled trials and secondary or post-trial analyses evaluating HRT in postmenopausal women, particularly women aged 65 years and older. Outcomes included cardiovascular, renal, and metabolic endpoints. Risk of bias was assessed using RoB 2 where applicable, and evidence was synthesized narratively. The review protocol was registered in PROSPERO (CRD420261338310).
Results: Of 1701 records identified, 6 reports met the inclusion criteria, all derived from three parent trials: the Women's Health Initiative Hormone Therapy Trials (WHI-HT), Early versus Late Intervention Trial with Estradiol (ELITE), and Kronos Early Estrogen Prevention Study (KEEPS). HRT effects varied by regimen and timing. In WHI-HT analyses, conjugated equine estrogens (CEE), alone or with medroxyprogesterone acetate (MPA), lowered low-density lipoprotein cholesterol (LDL-C) but increased triglycerides and systolic blood pressure; CEE plus MPA had a less favorable coronary profile than CEE alone. ELITE supported less favorable vascular effects with later initiation, while KEEPS showed neutral long-term findings. No trial was designed specifically for women aged ≥65 years, and evidence in this age group was limited to subgroup analyses of broader postmenopausal women. Additionally, no studies included renal outcomes.
Conclusion: Future prospective studies should evaluate cardiovascular, kidney, and metabolic outcomes across HRT regimens and timing in older postmenopausal women to guide individualized treatment decisions.

Keywords:  cardiovascular diseases; hormone replacement therapy; menopause; metabolic diseases; risk factors; systematic review

DOI:  https://doi.org/10.2147/CPAA.S581397
J Int Soc Sports Nutr. 2026 Dec 31. 23(sup1): 2711032

Effects of six weeks of guanidinoacetic acid supplementation with and without creatine monohydrate on cognitive function and markers of health in healthy adults.

Jisun Chun, Khatereh Babakhani, Drew E Gonzalez, Broderick Dickerson, Ryan J Sowinski, Chris J Rasmussen, Richard B Kreider.

   BACKGROUND: Guanidinoacetic acid (GAA) supplementation has been reported to increase brain creatine content more effectively than creatine monohydrate (CrM). However, the effects on cognitive function are unclear.
PURPOSE: The purpose of this proof-of-concept exploratory clinical trial was to determine whether GAA supplementation with and without CrM affects cognitive function and/or markers of health.
METHODS: In a double-blind, randomized, and counterbalanced manner, 58 healthy and active adults (33 females, 35.5 ± 14 years, 76.2 ± 14 kg) ingested a PLA (PLA, 2 × 6 g/d maltodextrin), GAA (2 × 1 g/d) + PLA (2 × 5 g/d), or GAA (2 × 1 g/d) + CrM (2 × 5 g/d) for six weeks. The participants donated fasting blood samples and completed a battery of tests and questionnaires assessing various aspects of function, mood, stress, sleep quality, and markers of health at baseline and after six weeks of supplementation. Data were analyzed using General Linear Model (GLM) multivariate and univariate with repeated measures, and mean changes from baseline with 95% confidence intervals, and Chi-squared analysis, and considered significant when the probability of error was 0.05 or less, and approaching significance (p > 0.05-p < 0.10).
RESULTS: GAA supplementation tended to improve overall reaction time (-241.8 ms [-533, 50], p = 0.10) while significant interaction effects were observed in overall reaction time (p = 0.031-330 ms [-629, -31]) and YES reaction time (-290 ms [-484, -96], p = 0.004) while recalled correct reaction time (-178 ms [-374, 21], p = 0.078) and recalled correct YES (7.4 % [-1, 15.8], p = 0.084) approached significance compared to PLA. Limited to no effects were observed on the Delayed Picture Recognition Task Test, Digit Vigilance Task Test, Corsi Block Task Test, or Stroop Color-Word Task Test. The amount of time engaged in moderate physical activity was significantly greater (p < 0.05) in the GAA group compared to PLA. Participants in the GAA group reported a lower frequency of controlling irritations (p = 0.036), and feeling like difficulties are mounting (p = 0.053) on the Perceived Stress Scale. Some positive and potentially undesirable effects were observed in sleep quality assessments. The quality of life assessment revealed that participants in the GAA group reported less frequent feelings of being worn out (p = 0.068) and that their health was excellent (p = 0.092) while those in the GAA + CrM group reported more frequent limitations when bending, kneeling, or stooping (p = 0.053), more often feeling full of life (p = 0.081), and less frequency in feeling downhearted and depressed (p = 0.066). No clinically meaningful changes were observed in blood markers or self-reported side effects among the groups.
CONCLUSION: Dietary supplementation with GAA (2 g/d) and the combination of CrM (10 g/d + GAA 2 g/d) for six weeks improved delayed verbal episodic recognition memory and retrieval speed and some measures of perceived stress, sleep quality, and quality of life. However, most cognitive tests were not affected, particularly when comparing the GAA to the PLA group; there were some inconsistencies in the findings, and several differences only approached significance. Additional research is needed before conclusions can be drawn. Clinical trial registration: ISRCTN68542582.

Keywords:  Dietary supplement; attention; memory; nootropic; recall; vigilance

DOI:  https://doi.org/10.1080/15502783.2026.2711032
Nutrients. 2026 Aug 25. pii: 2777. [Epub ahead of print]18(17):

Effects of a Combined Vitamin D3 and Docosahexaenoic Acid Intervention on Cognitive Function and Blood Pyroptotic Biomarkers in Older Adults with Mild Cognitive Impairment: A 12-Month Randomized, Double-Blind, Placebo-Controlled Trial.

Jing Yuan, Ruifang Yang, Hui Chen, Huichao Zhao, Xuan Chen, Ziyan Lou, Xinze Han, Fei Ma.

  Background: This study aimed to assess the effects of a combined vitamin D3 (VD3) and docosahexaenoic acid (DHA) intervention on cognitive function and blood pyroptotic biomarkers in older adults with mild cognitive impairment (MCI). Methods: In total, 360 participants with MCI were recruited, and randomly assigned into four groups: VD3 (800 IU/day), DHA (1 g/day), VD3+DHA (VD3 800 IU/day+DHA 1 g/day), and placebo. Cognitive function was evaluated by the Wechsler Adult Intelligence Scale-Revised in China (WAIS-RC), and blood biomarkers were measured by ELISA and Western blot at baseline, 6 months and 12 months. Linear mixed-effects models (LMMs) were employed to analyze longitudinal interaction effects on cognitive function and blood biomarkers. Structural equation modeling (SEM) was conducted to evaluate the parallel mediation effects of blood biomarkers on cognitive improvements. Results: A total of 355 participants completed the trial. Over the 12-month intervention, all intervention groups demonstrated significant improvements in cognitive function and reductions in five blood biomarkers (IL-1β, IL-18, NLRP3, Gasdermin D (GSDMD), cleaved caspase-1) compared to the placebo group (p < 0.05). Compared to each single intervention, the combined VD3 and DHA intervention yielded superior cognitive improvements in scores for full-scale IQ (FIQ), performance IQ (PIQ), verbal IQ (VIQ) and several subtests (information, comprehension, digit span, vocabulary, picture completion, block design, and picture arrangement), and significantly reduced five blood pyroptotic biomarkers (all p < 0.05). Path analysis revealed that longitudinal GSDMD reduction mediated the improvements in FIQ. Conclusions: A 12-month intervention with VD3, DHA, or their combination significantly improves cognitive function and mitigates pyroptosis, and the combined intervention showed superior benefits, potentially mediated by downregulating the protein GSDMD.

Keywords:  NLRP3 inflammasome; docosahexaenoic acid; mild cognitive impairment; pyroptosis; randomized controlled trial; vitamin D3

DOI:  https://doi.org/10.3390/nu18172777
Front Pharmacol. 2026 ;17 1849218

Synaptic mitochondrial dysfunction and Alzheimer's disease: from molecular mechanisms to therapeutic strategies.

Yuxin Wang, Weidong Wu, Lishuang Yan, Bo Zhang, Quan Li, Yanyan Zhou.

  The ability of AD treatments targeting classic pathological proteins to achieve meaningful clinical outcomes has been severely limited, shifting attention to the earlier upstream pathways that drive disease progression. Increasing evidence indicates that synaptic mitochondrial dysfunction is an early pathological event that directly contributes to synaptic loss and cognitive decline. This review focuses on how four interrelated pathologies-disrupted energy metabolism, calcium overload, imbalanced mitochondrial fission/fusion, and defective autophagy-converge to impair synaptic function and plasticity. Emerging therapeutic strategies aimed at protecting and restoring synaptic mitochondrial health, including mitochondria-targeted antioxidants, metabolic modulators, calcium signaling inhibitors, dynamics regulators, and autophagy inducers, are also examined. A central focus of the review is clinical translation: we summarize the preclinical evidence and critically evaluate major obstacles such as the lack of synapse-specific biomarkers, challenges in blood-brain barrier penetration and targeted delivery, and substantial patient heterogeneity. Rather than proposing a fully defined translational framework, we highlight the essential requirements for building one, centered on synaptic mitochondrial bioenergetics and quality control. Specifically, early and accurate biomarkers must be developed, patients should be stratified promptly, and rational combination therapies with complementary mechanisms need to be implemented. This organelle-centered perspective will clarify AD pathogenesis and help guide the development of next-generation neuroprotective therapies.

Keywords:  AD; Alzheimer’s disease; ROS; oxidative stress; synaptic mitochondrial dysfunction

DOI:  https://doi.org/10.3389/fphar.2026.1849218
J Gerontol A Biol Sci Med Sci. 2026 Sep 16. pii: glag225. [Epub ahead of print]

Adiposity and Cognitive Performance in Older Men and Women from the Study of Muscle, Mobility and Aging (SOMMA).

John J Dubé, Haley N Barnes, Zana M Ross, Neharika Murthy, Nikola Gligorijevic, Mahesh K Basantani, Divya Gupta, Cheehoon Ahn, Andrea M Brennan, Maria F Pino, Frederico G S Toledo, Maja Stefanovic-Racic, Paul M Coen, Peggy M Cawthon, Steven R Cummings, Stephen B Kritchevsky, Anne B Newman, Lauren M Sparks, Erin E Kershaw.

   BACKGROUND: Aging is accompanied by changes in body composition and cognition. Although adiposity has been linked to metabolic dysfunction and dementia risk, associations with specific cognitive domains in later life remain unclear.
METHODS: This cross-sectional study examined associations between adiposity and cognitive performance in 769 community-dwelling, healthy older adults (70-94 years) from the Study of Muscle, Mobility and Aging (SOMMA). Adiposity was assessed using anthropometric measures (body mass index, waist circumference) and MRI-derived regional fat volumes, including visceral and abdominal subcutaneous adipose tissue. Cognitive performance was evaluated using a screening measure (Montreal Cognitive Assessment), processing speed (Digit Symbol Coding Test), executive function (Trail Making Test B), and memory (California Verbal Learning Test-II Short Form). Multivariable linear regression models were sequentially adjusted for demographic, cardiometabolic, psychosocial, and behavioral factors.
RESULTS: Greater age was associated with lower adiposity and poorer cognitive performance (p < 0.05). Most adiposity measures were inversely associated with processing speed after adjustment for age, sex, race, and testing site (p < 0.05). These associations generally persisted after adjustment for cardiometabolic conditions and were attenuated after inclusion of education, depressive symptoms, and behavioral covariates. No significant associations were observed between adiposity and executive function. Memory outcomes showed modest, exploratory associations with abdominal subcutaneous adipose tissue measures only in fully adjusted models (p = 0.03-0.07).
CONCLUSIONS: In healthy older adults, adiposity is most consistently related to processing speed, whereas associations with memory and executive function are weaker or absent. Processing speed may be especially sensitive to adiposity-related differences. Longitudinal studies are needed to clarify temporal relationships.

Keywords:  Adipose tissue; Cognitive function; Human aging; SOMMA

DOI:  https://doi.org/10.1093/gerona/glag225
Molecules. 2026 Sep 05. pii: 3113. [Epub ahead of print]31(17):

Hydroxytyrosol as a Multitarget Neuroprotective Agent: Molecular Mechanisms, Pharmacokinetics and Therapeutic Potential in Neurodegenerative Diseases.

Pura Ballester-Navarro, Ana María García-Muñoz, Desirée Victoria-Montesinos, Pilar Zafrilla.

  Neurodegenerative diseases arise from interacting oxidative, inflammatory, mitochondrial, and proteostatic disturbances. Hydroxytyrosol (HT), an olive phenol, has been proposed as a multitarget neuroprotective compound. This narrative review integrates HT chemistry, parent/metabolite pharmacokinetics, blood-brain barrier (BBB) evidence, mechanisms, disorder-specific models, and human studies. Direct HT evidence is strongest for nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) activation and experimental modulation of α-synuclein; support for AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), mitochondrial protection, nuclear factor-kappa B (NF-κB)-related inflammation, and amyloid-β (Aβ) is predominantly preclinical, whereas tau, autophagic flux, and ubiquitin-proteasome effects remain preliminary. Oral HT is rapidly absorbed but extensively conjugated, and no study has quantified parent HT or its major metabolites in the human brain or cerebrospinal fluid after oral supplementation. Isolated-HT trials show systemic antioxidant or anti-inflammatory biomarker effects, while cognitive findings derive mainly from phenolic-rich olive matrices and cannot be assigned to HT alone. No disease-modifying efficacy has been established for isolated HT in Alzheimer's disease (AD), Parkinson's disease (PD), or related disorders. HT is therefore a mechanistically plausible candidate, but human brain exposure, dose-response, and efficacy require adequately powered disease-specific trials.

Keywords:  hydroxytyrosol; mitochondrial dysfunction; neurodegenerative diseases; nutraceuticals; oxidative stress

DOI:  https://doi.org/10.3390/molecules31173113
Nutrients. 2026 Sep 07. pii: 2936. [Epub ahead of print]18(17):

Effects of Nutritional Supplements on Inflammatory Biomarkers in Overweight and Obese Adults: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

Zhiyue Chen, Ailing Liu, Shuran Bian, Zhize Zhou, Dong Zhang.

  Background/Objectives: Obesity is frequently associated with chronic low-grade inflammation, which contributes to metabolic dysfunction. However, the comparative effects of nutritional supplements on inflammatory biomarkers in adults with overweight or obesity remain unclear. To address this gap, this paper presents a systematic review and network meta-analysis comparing 14 supplementation strategies for their effects on inflammatory biomarkers in this population. Methods: PubMed, Embase, EBSCO, Web of Science, and the Cochrane Library were searched for randomized controlled trials published between January 2000 and January 2026. A frequentist random-effects network meta-analysis was conducted. Effects were reported as mean differences (MDs) with 95% confidence intervals (CIs), and interventions were ranked using the surface under the cumulative ranking curve (SUCRA). The confidence in network estimates was assessed using the Confidence in Network Meta-Analysis (CINeMA) framework. Results: A total of 60 randomized controlled trials were included. Green tea extract (MD = -2.57, 95% CI [-3.99, -1.15]) and curcumin (MD = -1.75, 95% CI [-2.74, -0.76]) both significantly reduced IL-6 levels. Synbiotics (MD = -12.25, 95% CI [-16.7, -7.8]), curcumin (MD = -2.59, 95% CI [-3.83, -1.35]) and probiotics combined with omega-3 (MD = -6.19, 95% CI [-9.12, -3.26]) had a favorable effect on TNF-α. Probiotics combined with omega-3 (MD = -1.74, 95% CI [-3.03, -0.46]), synbiotics (MD = -1.19, 95% CI [-1.85, -0.53]), zinc (MD = -1.18, 95% CI [-2.24, -0.11]), and curcumin (MD = -1.11, 95% CI [-2.14, -0.07]) all reduced CRP levels. Synbiotics (MD = 15.37, 95% CI [12.13, 18.61]) increased adiponectin levels. In contrast, no nutritional supplement significantly reduced leptin levels. Exploratory meta-regression suggested that age, exercise co-interventions, and the proportion of male participants may partly explain heterogeneity in selected outcomes. Conclusions: Nutritional supplements showed biomarker-specific effects. Probiotics combined with omega-3 fatty acids, synbiotics, green tea extract, and curcumin may improve selected inflammatory biomarkers. However, differences in supplement dose, intervention duration, and participant characteristics warrant cautious interpretation and call for further high-quality trials.

Keywords:  inflammatory biomarkers; meta-analysis; nutritional supplements; obesity; overweight; randomized controlled trials

DOI:  https://doi.org/10.3390/nu18172936