bims-mistre 2026-03-08 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–03–08
eighteen papers selected by
Ellen Siobhan Mitchell, MitoQ

Hepatic mitochondrial signaling as a systemic hub: inter-organ communication networks in aging and aging-related diseases.
Early mitophagy activation by Urolithin A prevents, but late activation does not reverse, age-related cognitive impairment.
Growth Differentiation Factor-15 as a Clinical Biomarker of Frailty, Sarcopenia and Functional Decline: A Systematic Literature Review.
The Natural Flavonoid Isoscoparin Ameliorates Oxidative Stress and Mitochondrial Dysfunction in C. elegans and Macrophages.
Growth differentiation factor 15 and the risk of hip fracture in older adults.
Current Insights and Research Gaps in Selenium Supplementation for Metabolic Health: A Scoping Review.
Mitochondrial-Derived Vesicles: An Emerging Whisperer in Neurological Disorders.
The glycolytic metabolite phosphoenolpyruvate restricts cGAS-driven inflammation to promote healthy aging.
Beyond cellular distress: reframing GDF15 as a lipid-sensitive metabolic signal.
Propolis Supplementation and Metabolic Syndrome Components in Adults at Risk: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
HDAC6 regulates BACE1 stability and NLRP3 inflammasome activation in Alzheimer's disease.
A Randomized, Double-Blind, Two-Treatment, Two-Period, Crossover Study Investigating the Systemic Bioavailability of a Novel Cocrystal Ubiquinol Formulation Compared with a Ubiquinone Formulation in Healthy Adults.
Dietary restriction in aging and longevity.
Gut Microbiota Has the Potential to Improve Sarcopenic Obesity in Menopausal Women by Regulating Estrogen.
Synergistic Actions of Natural Compounds for Enhancing Cognitive and Physical Performance: A Narrative Review.
SIRT3 mediates mitochondrial protection and attenuates mtROS-TXNIP-NLRP3 signaling activation in dry eye disease.
ATP bioenergetics and fatigue in young adults with and without major depression.
Mitochondrial complex-derived ROS induces lysosomal dysfunction and impairs autophagic flux in human cells carrying the APOE4 allele.

Front Cell Dev Biol. 2026 ;14 1745201

Hepatic mitochondrial signaling as a systemic hub: inter-organ communication networks in aging and aging-related diseases.

Yishuo Ji, Ying Wang, Xiaowei Yu, Yi Jin, Kai Zhao, Yue Hu, Zhenglin He.

  Aging and aging-related diseases are increasingly viewed as systemic disorders arising from disrupted inter-organ communication, yet the mechanisms linking local metabolic stress to organism-wide dysfunction remain unclear. The liver occupies a central position in this network, but how hepatic mitochondrial stress is translated into circulating signals that remodel distant tissues is incompletely understood. Here, we synthesize evidence identifying hepatic mitochondria as a systemic signaling hub that integrates metabolic and inflammatory stress and disseminates blood-borne cues during aging. We focus on three major classes of mitochondrial outputs: UPRmt-driven mitokines, including fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15); metabolites generated through mitochondrial metabolic reprogramming; and mitochondrial danger signals such as mitochondrial reactive oxygen species (mtROS) and oxidized mitochondrial DNA (mtDNA). These signals act through endocrine, metabolic, and immune pathways to reshape mitochondrial function, inflammation, and energy homeostasis across multiple organs. We further discuss how aging shifts hepatic mitochondrial signaling from adaptive to maladaptive states and emphasize that liver-centered regulation operates within bidirectional networks involving the gut, skeletal muscle, and immune system. Finally, we outline translational challenges and potential strategies for modulating hepatic mitochondrial outputs to restore systemic homeostasis in aging and aging-related diseases.

Keywords:  UPRmt; aging; diseases; hepatic mitochondria; inter-organ communication; mitokines; mtDNA; mtROS

DOI:  https://doi.org/10.3389/fcell.2026.1745201
NPJ Aging. 2026 Mar 05.

Early mitophagy activation by Urolithin A prevents, but late activation does not reverse, age-related cognitive impairment.

Claudia Jara, Leslye Venegas-Zamora, Han S Park-Kang, Matías Lira, Micaela Ricca, Sebastian Valenzuela, Cheril Tapia-Rojas.

The hippocampus is crucial to learning and memory, functions that decline with age due to impaired mitochondrial bioenergetics and reduced mitophagy, resulting in the accumulation of dysfunctional mitochondria and increased susceptibility to neurodegeneration. Urolithin A (UA), a natural mitophagy activator derived from polyphenols, has demonstrated benefits in Alzheimer's disease models; however, its role in normal aging remains unclear. Here, we investigated whether UA can prevent or reverse hippocampal dysfunction by enhancing mitophagy and mitochondrial function. Two mouse models were used: 18-month-old C57BL/6 mice with established mitochondrial and cognitive deficits, and 5-month-old SAMP8 mice, an accelerated aging with cognitive decline starting from 6 months of age. UA was administered for 8 weeks, followed by assessments of ATP production, mitochondrial dynamics, mitophagy markers, synaptic proteins, and memory. In C57BL/6 mice, UA increased ATP, boosted proteins associated with fusion, antioxidant defense, and biogenesis, and reduced phosphorylated tau; however, these changes did not restore memory. In contrast, SAMP8 mice showed stronger effects: ATP rose sharply, mitochondrial stress and aberrant proteins decreased, and cognitive performance improved. These findings highlight UA effects as a preventive therapeutic agent, but are insufficient to reverse established cognitive decline, suggesting early mitophagy activation is critical to mitigate brain aging and neurodegeneration.

DOI: https://doi.org/10.1038/s41514-026-00351-3
Ageing Res Rev. 2026 Mar 03. pii: S1568-1637(26)00077-2. [Epub ahead of print] 103085

Growth Differentiation Factor-15 as a Clinical Biomarker of Frailty, Sarcopenia and Functional Decline: A Systematic Literature Review.

Ainsley Ryan Yan Bin Lee, Vidhya S Nachammai, Anjin Hong, Amanda Weiling Tan, Chun En Yau, Chen Ee Low, Reshma Aziz Merchant.

   BACKGROUND: With an aging population globally, prevention of frailty and sarcopenia will become a public health priority. Growth Differentiation Factor-15 (GDF-15), a stress-responsive cytokine of the TGF-β superfamily, has emerged as a promising biomarker linking mitochondrial dysfunction, cellular senescence, and systemic inflammation to biological and phenotypic aging.
OBJECTIVES: This systematic literature review systematically synthesizes the clinical evidence on GDF-15 as a biomarker of frailty, sarcopenia, and physical function, highlighting patterns, gaps, and the biological plausibility of its role as a predictive marker and therapeutic target.
METHODS: Following PRISMA guidelines, we searched CENTRAL, Embase, MEDLINE, and PubMed up to February 2026. Studies involving adult human participants with measured serum GDF-15 levels and assessments of frailty or sarcopenia were included. Data were extracted and grouped thematically by population type, study design, and outcome domains. Narrative synthesis was used to compare findings and explore heterogeneity.
RESULTS: From 1027 records, 35 studies were included, spanning community-dwelling adults, hospitalized patients, and individuals with cardiovascular, metabolic, gastrointestinal, and respiratory diseases. Elevated GDF-15 levels were consistently associated with poorer physical performance and greater frailty severity. Longitudinal studies suggested predictive value for future functional decline, although associations with sarcopenia were less consistent. Sex-specific variations and methodological heterogeneity, including assay techniques and diagnostic criteria, were key sources of variability. Interventional studies demonstrated limited modulation of GDF-15 levels through physical activity alone.
CONCLUSIONS: These findings support the integration of GDF-15 into precision geriatric care, though further longitudinal and interventional studies, including those evaluating the incremental value of adding GDF-15 to existing screening tools for frailty, sarcopenia, and functional status, are required to establish its clinical utility.

Keywords:  Growth Differentiation Factor 15; Physical, function; frailty; sarcopenia, handgrip strength

DOI:  https://doi.org/10.1016/j.arr.2026.103085
Biol Pharm Bull. 2026 ;49(3): 429-437

The Natural Flavonoid Isoscoparin Ameliorates Oxidative Stress and Mitochondrial Dysfunction in C. elegans and Macrophages.

Kui Wang, Lei Zhang, Guang-Cong Liang, Xue-Mei Duan, Chen Zeng, Gui-Juan Jin, Yong-Hua Tan.

  The natural flavonoid isoscoparin exhibits potent antioxidant activity, but its protective mechanisms against oxidative stress and mitochondrial dysfunction remain incompletely understood. This study investigated the effects of isoscoparin in Caenorhabditis elegans and lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. In C. elegans, isoscoparin significantly reduced intracellular reactive oxygen species (ROS) levels and enhanced resistance to paraquat-induced oxidative stress. These effects were associated with upregulation of antioxidant genes (daf-16, skn-1, sod-3, gst-4, ctl-1, ctl-2). In macrophages, isoscoparin not only enhanced the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) while reducing malondialdehyde (MDA) content but also attenuated LPS-induced mitochondrial ROS generation. Furthermore, isoscoparin restored mitochondrial respiratory function by improving basal and maximal respiration, ATP production, and spare respiratory capacity. It also stabilized mitochondrial membrane potential and restored the expression of electron transport chain complexes I-V. These findings demonstrate that isoscoparin alleviates oxidative stress through dual mechanisms: enhancing antioxidant defense via conserved pathways and directly protecting mitochondrial integrity. This study highlights the potential of isoscoparin as a therapeutic candidate for oxidative stress-related diseases.

Keywords:  Caenorhabditis elegans; antioxidant defense; isoscoparin; macrophage; mitochondrial dysfunction; oxidative stress

DOI:  https://doi.org/10.1248/bpb.b25-00654
JBMR Plus. 2026 Apr;10(4): ziaf192

Growth differentiation factor 15 and the risk of hip fracture in older adults.

Lorenza Mattia, Sheena Patel, Katey Webber, Giuseppe Pugliese, Steven R Cummings, Richard Eastell.

  Growth differentiation factor 15 (GDF15) is a protein that is produced by senescent cells during the aging process. Its level in blood increases with age and is associated with an increased risk of several age-related diseases and mortality. We measured GDF15 level in serum archived 1174 men and women aged between 70 and 79 yr in the Health Aging and Body Composition study who had measurements of BMD of the hip, markers of bone turnover (PINP and CTX) and tested for several physical functions (6 m gait speed, standing balance and grip strength, BMI, and appendicular lean mass) and falls, and were followed-up for incident fracture. Cox proportional hazard models were used to estimate hip fracture risk by increasing GDF15 quartiles. The mean GDF15 was significantly higher in men than in women (p < .0001) and the level significantly increased with age, slower gait speed, lower standing balance test time, and lower handgrip strength. During 11.5 (SD 4.5) yr of follow-up, 93 (8%) of the participants suffered a hip fracture and the risk was higher among women (p < .015), associated with older age, lower BMI, lower FN and TH BMD, lower appendicular lean mass, and weaker grip strength. In the unadjusted hazard model participants in the highest quartile of GDF15 had a 2-fold increased hip fracture risk (HR 2.12, p < .014) that remained significant after adjustment for age and sex (p < .037). However, the association was no longer statistically significant after adjusting for grip strength (HR 1.8, 95% CI: 0.97-3.34; p < .06). In conclusion, increased GDF15 is a predictor of hip fractures. This relationship might be partially mediated by muscle function and low lean mass but not BMD.

Keywords:  aging; growth differentiation factor 15; handgrip; hip fracture; muscle

DOI:  https://doi.org/10.1093/jbmrpl/ziaf192
Nutr Rev. 2026 Feb 28. pii: nuag005. [Epub ahead of print]

Current Insights and Research Gaps in Selenium Supplementation for Metabolic Health: A Scoping Review.

Linda Morales-Juárez, Astrid Domínguez-Uscanga, Janet A Gutiérrez-Uribe, Diego A Luna-Vital, Anayansi Escalante-Aburto.

  Selenium plays a crucial role in maintaining metabolic health, providing antioxidant protection, and modulating inflammation. Further clarification of the physiological functions and pathological relevance of selenium is necessary to increase understanding of its therapeutic potential through supplementation and to determine the most effective strategies across different populations and metabolic conditions. We sought to systematically map and synthesize existing evidence on the effects of selenium supplementation on inflammation, oxidative stress, and glucose-lipid metabolism in adult populations, and to identify knowledge gaps that hinder the establishment of safe and effective selenium dosing guidelines. A scoping review was conducted based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines, in which we searched for the major electronic databases to identify clinical trials that evaluated the effects of selenium supplementation on standard features of metabolic disease among diverse adult population groups. Improvements in metabolic markers were observed, particularly in studies addressing diabetes and insulin resistance (up to a 26% reduction in Homeostatic Model Assessment of Insulin Resistance [HOMA-IR])), and inflammation (with up to a 62.4% reduction in high-sensitivity C-reactive protein [hs-CRP]). The benefits were seen in reported studies with intervention durations of 12 weeks or longer. In limited studies, selenium had neutral effects in a trial of polycystic ovary syndrome (PCOS) and an adverse effect in 1 postmenopausal trial, indicating that results in these groups remain inconclusive. Co-supplementation with probiotics or antioxidants had beneficial effects in some studies. Selenium supplementation has been observed to improve insulin sensitivity, lower hs-CRP, and enhance antioxidant defenses, particularly in adults with diabetes or insulin resistance, while effects in PCOS and postmenopausal women remain equivocal. Because both deficiency and excess of selenium can be harmful, dosing must be guided by baseline selenium status. Harnessing this narrow therapeutic window could enhance metabolic care, but long-term, well-controlled trials are still needed to define optimal regimens and clarify who stands to benefit most.

Keywords:  inflammation; metabolic disorders; obesity; scoping review; selenium; supplementation

DOI:  https://doi.org/10.1093/nutrit/nuag005
Eur J Neurosci. 2026 Mar;63(5): e70449

Mitochondrial-Derived Vesicles: An Emerging Whisperer in Neurological Disorders.

Nermeen Z Abuelezz, Fayza Eid Nasr, Amira Emad Abd El Aziz, Mariam K Ahmed, Nesrine S El Sayed.

  Mitochondrial dysfunction is a pivotal feature in the pathogenesis of various neurological and neurodegenerative disorders. The brain, with its high metabolic demands, is particularly vulnerable to impaired mitochondrial function, leading to oxidative stress, disturbed calcium homeostasis, and hyperactivated microglial responses. Mitochondrial disturbances majorly contribute to neuronal damage, synaptic dysfunction, and cognitive decline, making mitochondria a crucial target for therapeutic intervention in brain disorders. In this context, mitochondrial-derived vesicles (MDVs) are increasingly emerging as a novel aspect of mitochondrial biology with significant implications for brain health and disease. Prior to mitophagy, MDVs are released from stressed mitochondria, incorporating either healthy or damaged mitochondrial components as an earlier defense mechanism to maintain mitochondrial integrity and homeostasis. Furthermore, MDVs contribute to intercellular communication and extracellular neuroinflammation signaling, potentially influencing the progression of neurological disorders. This review provides a thorough overview of MDVs' subpopulations, highlighting the most recently reported MDVs roles across multiple neurological disorders and exploring their potential in diagnostic and therapeutic settings. Additionally, we further analyze the current limitations that hinder broader clinical applications of MDVs and present future perspectives and key recommendations to overcome these obstacles, aiming to enhance their effectiveness in diagnosis, therapy, and brain-targeted drug delivery.

Keywords:  mitochondrial communication; mitochondrial dysfunction; mitophagy; neurodegenerative disorders; vesicles

DOI:  https://doi.org/10.1111/ejn.70449
Nat Aging. 2026 Mar 06.

The glycolytic metabolite phosphoenolpyruvate restricts cGAS-driven inflammation to promote healthy aging.

Zengqing Song, Huaibin Hu, Wanpeng Zhang, Xincheng Zheng, Liyun Liang, Bing Zhao, Guangping Song, Jianing Li, Sen Li, Yuqi Wen, Biyu Zhang, Wen Wang, Guozhen Deng, Cunjin Zhang, Hua Jiang, Supei Hu, Haiqing Tu, Min Wu, Huiyan Li.

Aging involves multiple detrimental changes in the systemic milieu, leading to functional deterioration and age-related diseases. However, the potential self-protective adaptive alterations during aging remain underexplored. Here we show that phosphoenolpyruvate (PEP), a glycolytic metabolite, acts as a protective factor against age-related chronic inflammation. Longitudinal analyses in mice and humans reveal a biphasic PEP trajectory, characterized by initial accumulation followed by progressive decline. Blocking PEP accumulation exacerbates inflammation and accelerates aging phenotypes, whereas PEP administration before its decline promotes healthy aging in mice. In aged humans, high PEP levels strongly correlate with lower inflammation and healthier traits. Mechanistically, PEP acts as an endogenous inhibitor of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway by competitively binding to cGAS. Moreover, PEP alleviates neuroinflammation and improves cognitive function in an Alzheimer's disease mouse model. Thus, our findings define PEP accumulation as an evolutionarily conserved geroprotective mechanism, positioning PEP as a promising intervention for aging and associated diseases.

DOI: https://doi.org/10.1038/s43587-026-01087-1
Curr Opin Lipidol. 2026 Apr 01. 37(2): 45-51

Beyond cellular distress: reframing GDF15 as a lipid-sensitive metabolic signal.

Dongdong Wang, Logan K Townsend, Gregory R Steinberg.

   PURPOSE OF REVIEW: Growth differentiation factor-15 (GDF15) is widely described as a hormone that conveys somatic distress to the brain, yet this framework does not explain why GDF15 is elevated in many common metabolic states. Recent work shows that GDF15 rises most consistently when fatty acid availability exceeds mitochondrial and endoplasmic reticulum capacity. This review synthesizes emerging evidence that positions GDF15 as an endocrine sensor of lipid load rather than a general stress signal.
RECENT FINDINGS: Across acute dietary lipid exposure, endogenous lipolysis during fasting, chronic overnutrition, ketogenic feeding, and mitochondrial dysfunction, free fatty acids activate lipid-sensitive transcriptional pathways that induce GDF15 expression in kidney, liver, intestine, and adipose tissue macrophages. Once elevated, GDF15 engages hindbrain glial-cell-derived neurotrophic factor family receptor α-like (GFRAL) signaling to increase sympathetic outflow, promote whole-body fatty acid oxidation, redistribute lipid burden, and improve metabolic flexibility. These effects occur independently of reduced food intake and reflect coordinated actions across liver, adipose tissue, and skeletal muscle.
SUMMARY: Viewing GDF15 as a lipid-responsive hormonal signal reshapes our understanding of its physiological role and provides new insight into metabolic adaptations to lipid overload. This pattern suggests that GDF15 is part of a feedback system that attempts to match fatty acid oxidation with supply, analogous to how carbohydrate ingestion stimulates insulin to promote glucose oxidation and suppress hepatic glucose production to restore euglycemia. Within this framework, individual tissues respond in complementary ways to reduce lipid burden and maintain metabolic balance. Understanding this coordinated lipid-responsive network highlights opportunities to target the GDF15 pathway in disorders characterized by impaired fatty acid handling including obesity, type 2 diabetes, cardiovascular disease, cancer cachexia and metabolic dysfunction-associated steatotic liver disease (MASLD).

Keywords:  GFRAL; MASH; MASLD; adipose tissue; diabetes; fatty acids; growth differentiation factor-15; lipotoxicity; mitochondrial stress; triglycerides

DOI:  https://doi.org/10.1097/MOL.0000000000001025
Health Sci Rep. 2026 Mar;9(3): e71909

Propolis Supplementation and Metabolic Syndrome Components in Adults at Risk: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Safia Obaidur Rab, Mudher Kadhem, Malathi H, Swati Mishra, Ishant Arora, Mehran Nouri.

   Background and Aims: Propolis is a natural resinous substance produced by bees, recognized for its antioxidant and anti-inflammatory properties. Previous clinical trials have reported inconsistent results regarding its effects on various components of metabolic syndrome (MetS). To address this, we conducted a comprehensive meta-analysis to evaluate the impact of propolis on components of MetS in adults at risk.
Methods: A systematic search was conducted in PubMed, Web of Science, Cochrane, Scopus, ISI Web of Science, and Google Scholar up to July 2025. This search aimed to identify all randomized controlled trials (RCTs) that examined the effects of propolis supplementation on various components of MetS in propolis on components of MetS in adults at risk. Relevant studies were included in this systematic review and meta-analysis based on keywords related to propolis and MetS. The weighted mean difference (WMD) was calculated using a random-effects model.
Results: A total of 20 RCTs involving 1091 participants were included in this meta-analysis. The results indicated that propolis supplementation significantly reduced fasting blood sugar (FBS) (WMD: -7.93 mg/dL, 95% CI: -12.37 to -3.50, p < 0.001) and triglyceride (TG) levels (WMD: -12.32 mg/dL, 95% CI: -21.08 to -3.56, p = 0.006) when compared to the control group. However, the analysis revealed that propolis did not have a significant effect on waist circumference, high-density lipoprotein cholesterol levels, or on either systolic or diastolic blood pressure.
Conclusion: Supplementation with propolis significantly lowered FBS and TG levels in individuals with MetS risk factors. However, there were no significant effects showed on other components of MetS. These findings suggest potential benefits for glycemic and TG control, but more high-quality clinical trials with extended follow-up periods are needed to confirm and further investigate these results.

Keywords:  bee glue; metabolic syndrome; meta‐analysis; propolis; systematic review

DOI:  https://doi.org/10.1002/hsr2.71909
Brain. 2026 Mar 06. pii: awag089. [Epub ahead of print]

HDAC6 regulates BACE1 stability and NLRP3 inflammasome activation in Alzheimer's disease.

Jeongmi Lee, Yongeun Cho, Bo Youn Choi, Hark Kyun Kim, Yeongyeong Lee, Eunae Kim, Jihoon Han, Jae Hoon Sul, Jun-Sik Kim, Seung Hyun Baek, Yoonsuk Cho, Jinsu Park, Gahee Bahn, Han-Gyu Bae, Jae Hyun Jun, Mitchell K P Lai, Thiruma V Arumugam, Dong-Gyu Jo.

  Alzheimer's disease (AD) is marked by amyloid-β (Aβ) accumulation, tau pathology, and neuroinflammation. The β-site APP cleaving enzyme 1 (BACE1) is a key driver of Aβ production, while the NLRP3 inflammasome mediates microglial inflammatory responses. Histone deacetylase 6 (HDAC6), a cytoplasmic deacetylase, is upregulated in AD, yet its role in disease mechanisms remains unclear. Here, we show that HDAC6 promotes BACE1 protein stability through direct deacetylation of its C-terminal lysine (K501), thereby increasing Aβ production. HDAC6 also facilitated NLRP3 inflammasome activation in microglia, increasing IL-1β production in a catalytic domain-dependent manner. HDAC6 deficiency in 5xFAD mice reduced BACE1 accumulation, Aβ deposition, ASC speck formation, and IL-1β levels, accompanied by improved cognitive performance. Transcriptomic profiling further revealed downregulation of disease-associated microglial and neurotoxic astrocyte signatures alongside enrichment of synaptic pathways. These findings establish HDAC6 as a dual regulator of Aβ production and neuroinflammation, highlighting it as a promising therapeutic target in AD.

Keywords:  Alzheimer’s disease (AD); BACE1; HDAC6; NLRP3 inflammasome

DOI:  https://doi.org/10.1093/brain/awag089
Clin Pharmacol Drug Dev. 2026 Mar;15(3): e70042

A Randomized, Double-Blind, Two-Treatment, Two-Period, Crossover Study Investigating the Systemic Bioavailability of a Novel Cocrystal Ubiquinol Formulation Compared with a Ubiquinone Formulation in Healthy Adults.

Xuefeng Mei, Bingqing Zhu, Kshitij Soni, Kishore Kasaraneni, Nirav Panchal.

  Coenzyme Q10 (CoQ10) is a naturally occurring biochemical cofactor found in all human cell membranes in two interconvertible forms: oxidized ubiquinone and reduced ubiquinol. Clinical studies indicate that different CoQ10 formulations have different absorption rates, highlighting research comparing their systemic bioavailability. This study compared the oral bioavailability of cocrystal formulation soft gels (test product), a novel ubiquinol formulation, and ubiquinone formulation (reference product) in a randomized, double-blind, two-period crossover study with 12 healthy subjects under fasting conditions. The secondary objective of this study was to evaluate the safety and tolerability of the ubiquinol formulation. The pharmacokinetic analyses indicated that the test ubiquinol formulation demonstrated substantially higher relative systemic bioavailability compared with the ubiquinone reference. The geometric mean ratios (test/reference) for baseline-corrected peak plasma concentration (Cmax) and area under the curve from zero to last quantifiable time (AUC0-t) were 2.20 and 2.01, respectively, with 90% confidence intervals of 1.59-3.04 and 1.51-2.70. The geometric mean ratio for AUC from time zero to infinity (AUC0-∞) was 3.43 (90% CI: 1.47-8.00). No adverse events were reported in this small pilot study for either of the formulations. These findings demonstrate that ubiquinol has a better systemic bioavailability than ubiquinone, supporting the novel formulation's potential as a promising alternative to traditional CoQ10 supplements.

Keywords:  CoQ10 supplementation; bioavailability; coenzyme Q10; pharmacokinetics; ubiquinol cocrystal; ubiquinone

DOI:  https://doi.org/10.1002/cpdd.70042
Nat Aging. 2026 Mar 06.

Dietary restriction in aging and longevity.

Tomas Schmauck-Medina, Sofie Lautrup, Andrea Di Francesco, Sarah J Mitchell, Christoffer Clemmensen, Linda Partridge, George S Roth, Rozalyn M Anderson, Julie A Mattison, Rafael de Cabo, John R Speakman, Arlan Richardson, Donald K Ingram, Richard Weindruch, Mark P Mattson, Evandro F Fang.

Different types of dietary restriction (DR) have been practiced by humans for religious and medical purposes for millennia, but only during the past three decades has the scientific study of DR at cellular and molecular levels proliferated. Here we review the evidence testing a variety of DR paradigms in the context of aging, focusing on mammalian findings. We discuss potential DR mimetics that modulate autophagy, FGF21, AMPK, mTORC1, NAD+ metabolism, SIRTs, GLP-1R and other pathways as well as organismal and cellular adaptations to DR, including the roles of fasting, hunger, changes in body temperature and fat loss. We also consider the potential negative effects of DR such as increased vulnerability to infections and impaired wound healing. Further, we discuss preclinical evidence evaluating the potential of DR to improve healthspan and treat, prevent or delay age-related diseases including cancer, cardiovascular diseases and neurodegeneration. Finally, we consider the future opportunities for translation, and the challenges inherent to this complex research field.

DOI: https://doi.org/10.1038/s43587-026-01091-5
Int J Womens Health. 2026 ;18 589117

Gut Microbiota Has the Potential to Improve Sarcopenic Obesity in Menopausal Women by Regulating Estrogen.

Yuanyuan Jin, Tao Wang, Dan Liao, Xiaoqing Jin.

   Background: Sarcopenic obesity (SO) in menopausal women, characterized by concurrent skeletal muscle loss and visceral adiposity, is primarily driven by estrogen deficiency. Emerging evidence suggests that the gut microbiota, through its "estrobolome" function, may significantly influence SO pathogenesis by modulating estrogen metabolism and muscle-adipose crosstalk.
Objective: To systematically review the mechanisms linking the gut microbiota, estrogen metabolism, and SO risk in menopausal women.
Methods: We synthesized findings from animal models, mechanistic studies, and small-scale human trials investigating the microbiota-estrogen-muscle/adipose axis.
Results: Menopause reduced the abundance of the gut microbial β-glucuronidase, impairing enterohepatic estrogen recirculation. Dysbiosis activates the LPS-TLR4 pathway, promoting muscle catabolism via MuRF1 up-regulation and adipose inflammation. Short-chain fatty acids enhance insulin sensitivity through GLP-1 stimulation. Population studies have demonstrated reduced microbiota diversity and altered Firmicutes/Bacteroidetes ratios in postmenopausal women, which correlates with systemic inflammation and metabolic dysfunction. Intervention studies using combined soy isoflavones and probiotics have shown lipid benefits, but muscle effects remain unevaluated.
Conclusion: The gut microbiota-estrogen axis is a promising therapeutic target for menopausal SO; however, current evidence is limited to preclinical models and small human trials. Rigorous large-scale randomized controlled trials are essential to establish efficacy and safety before microbiota-based interventions can be recommended as adjunctive therapies.

Keywords:  estrobolome; gut microbiota; menopause; sarcopenic obesity; therapeutic implications

DOI:  https://doi.org/10.2147/IJWH.S589117
Cureus. 2026 Jan;18(1): e102674

Synergistic Actions of Natural Compounds for Enhancing Cognitive and Physical Performance: A Narrative Review.

Raghav Panda, Harvey N Mayrovitz.

  Energy drinks are widely consumed for cognitive and physical enhancement, yet most commercial formulations rely on a narrow mechanism: rapid stimulation from synthetic caffeine combined with artificial sweeteners. This stimulant-centric strategy overlooks the multidimensional physiology underlying sustained human energy, which emerges from interactions among neurocognitive activation, nitric oxide-mediated vascular function, mitochondrial ATP production, and metabolic homeostasis. This narrative review synthesizes evidence on naturally derived compounds that influence these pathways, including guayusa, guarana, Alpinia galanga, theobromine, L-citrulline, beetroot extract, cordyceps, and niacin, as well as natural sweeteners such as monk fruit and stevia. Evidence suggests that these agents may support cognitive performance, oxygen efficiency, vascular perfusion, and cellular energy capacity through mechanisms distinct from those of traditional energy drinks. However, heterogeneity across extract standardization, dosing, and study design limits the ability to draw definitive conclusions. A system-level understanding of energy physiology may guide the development of formulations better aligned with long-term cardiovascular, cognitive, and metabolic health.

Keywords:  beetroot; cordyceps; guayusa.; l-citrulline; monk fruit; natural stimulants; niacin; nitric oxide; non-nutritive sweeteners; stevia

DOI:  https://doi.org/10.7759/cureus.102674
Exp Eye Res. 2026 Mar 04. pii: S0014-4835(26)00116-8. [Epub ahead of print] 110960

SIRT3 mediates mitochondrial protection and attenuates mtROS-TXNIP-NLRP3 signaling activation in dry eye disease.

Di Zhang, Yun He, Fan Yang, Yiran Chu, Jiaxuan Jiang, Boda Li, Zeying Chen, Qi Zhang, Kai Hu.

   BACKGROUND/AIM: Dry eye disease (DED) is a chronic inflammatory disorder of the ocular surface in which mitochondrial dysfunction and oxidative stress have been increasingly implicated, yet the molecular mechanisms linking mitochondrial redox imbalance to inflammatory signaling remain unclear. This study aimed to investigate the role of Sirtuin 3 (SIRT3)-mediated mitochondrial protection in DED and to elucidate the involvement of the mtROS-TXNIP-NLRP3 signaling pathway.
METHODS: We established animal model of benzalkonium chloride (BAC) induced mice, and cellular model of hypertonic medium-challenged human corneal epithelial cells (HCE-Ts). In these models, we evaluated the expression of proteins related to the TXNIP-NLRP3 pathway by western blot. The mitochondrial function was assessed by detecting mtROS with fluorescence staining, measuring ATP production with chemiluminescence, detecting mitochondrial membrane potential with the JC-1 probe, and observing mitochondrial ultrastructure with transmission electron microscope. Changes in oxidative stress indicators were measured using a microplate reader.
RESULTS: Our study found that TXNIP is a key link between mitochondrial redox imbalance and activation of the NLRP3 inflammasome pathway in HCE-Ts, giving the evidence of mtROS-TXNIP-NLRP3 pathway activation in DED. Overexpression of SIRT3 mitigated mitochondrial dysfunction and attenuated the downstream inflammatory pathway in the progression of DED. In vivo, the application of Honokiol (HKL, a reported SIRT3 activator) eye drops, can improve mitochondrial function and attenuate the TXNIP-NLRP3 pathway in mice.
CONCLUSIONS: SIRT3 provided mitochondrial protection and attenuated the activation of mtROS-TXNIP-NLRP3 signaling in DED.

Keywords:  Mitochondrial function; SIRT3; TXNIP; dry eye disease

DOI:  https://doi.org/10.1016/j.exer.2026.110960
Transl Psychiatry. 2026 Mar 04.

ATP bioenergetics and fatigue in young adults with and without major depression.

Kathryn R Cullen, Susannah J Tye, Bonnie Klimes-Dougan, Hannes M Wiesner, Roger B Varela, Brooke Morath, Lin Zhang, Wei Chen, Xiao-Hong Zhu.

Fatigue is a pervasive and difficult-to-treat symptom of major depressive disorder (MDD) that contributes to disability. Understanding this problem in its earlier stages will be critical for averting long-term negative outcomes. To investigate the molecular roots of fatigue in early-stage depression, the current work measured bioenergetic mechanisms, with a focus on adenosine triphosphate (ATP), in brain and blood cells in young adults with MDD versus healthy controls (HC). To measure ATP concentration and ATP production rate in the visual cortex, we utilized 31P magnetic resonance spectroscopy imaging with magnetization transfer (31P MRSI-MT) at 7 Tesla, with and without gamma-ATP resonance saturation. ATP level was also measured in peripheral blood mononuclear cells (PBMCs) at rest and after serial addition of mitochondrial inhibitors. Out of 25 participants (mean age 21.8 years), usable data were available for 18 participants for imaging (9 per group); 24 for PBMCs (13 HC; 11 MDD). The MDD group demonstrated higher ATP production rate in the visual cortex than HC, which correlated positively with Fatigue Severity Scale (FSS) scores. ATP concentrations in PBMCs were higher in MDD than HC, and also correlated with FSS scores. After mitochondrial uncoupling, PBMCs in the MDD group had a lower capacity for ATP production than HC. For the first time, we demonstrate an ATP biosignature of fatigue in young adults with MDD that is visible in both brain and peripheral blood. The findings suggest a compensatory mechanism that occurs early in the disease stage.

DOI: https://doi.org/10.1038/s41398-026-03904-y
Biochim Biophys Acta Mol Basis Dis. 2026 Mar 03. pii: S0925-4439(26)00060-8. [Epub ahead of print] 168211

Mitochondrial complex-derived ROS induces lysosomal dysfunction and impairs autophagic flux in human cells carrying the APOE4 allele.

Sandra A Niño, Oskar Barrios-Camus, Eduardo Silva-Pavez, J César Cárdenas, Christian González-Billault.

  The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer's disease (sAD), yet its cell-autonomous effects remain poorly understood. While young, asymptomatic APOE4 carriers exhibit abnormal brain metabolism, the mechanistic link between mitochondrial dysfunction and lysosomal-autophagic failure remains unclear. In this study, we conducted a comprehensive analysis of primary human fibroblasts from APOE3 controls, APOE4, and sAD donors to assess mitochondrial bioenergetics, oxidative stress, autophagy, and lysosomal function. APOE4 fibroblasts displayed increased mitochondrial content-associated markers (PGC1α, mtDNA) accompanied by reduced respiratory capacity, elevated proton leak, and excessive mitochondrial ROS. In parallel, APOE4 fibroblasts showed impaired autophagic flux and reduced LC3-TOMM20 colocalization, indicating defective mitophagy. Lysosomal proteolytic activity, assessed using DQ-BSA, was significantly reduced and remained unresponsive under to starvation, in contrast to the partial recovery observed in sAD cells. Pharmacological targeting of mitochondrial ROS with site-specific inhibitors revealed that complex III-derived ROS is the predominant driver of redox stress in APOE4 fibroblasts, while complex I contributes primarily in sAD. Notably, selective inhibition of complex III-derived ROS with S3QEL restored lysosomal degradation, autophagic flux, and mitochondrial respiration in APOE4 cells. Together, these findings demonstrate that mitochondrial oxidative stress disrupts the mitochondria-lysosome axis in an APOE4-specific manner, revealing early and mechanistically distinct vulnerabilities that may precede neurodegeneration. Our results challenge the notion that APOE4 merely amplifies AD pathology and instead identity site-specific redox signaling as a promising target for allele-informed interventions.

Keywords:  APOE4; Autophagy; Human fibroblasts; Lysosome; Mitochondria; Mitochondrial complex III; S3QEL

DOI:  https://doi.org/10.1016/j.bbadis.2026.168211