bims-mistre 2026-08-23 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–08–23
seventeen papers selected by
Ellen Siobhan Mitchell, MitoQ

Mitochondrial Dysfunction as a Central Hub of Aging: From Molecular Cascades to Inter-Organ Communication Networks.
The role of mitochondrial dysfunction and genetics in female infertility and premature ovarian insufficiency.
17α-Estradiol Confers Limited Protection Against APOE4 Phenotypes in Middle-Aged Female Mice.
Cell-Free Circulating Mitochondrial DNA: A Biomarker of Physiological Stress and Adaptation in Athletes.
Aged Mitochondrial DNA Is Associated With Aberrant Acute Exercise-Induced Redox Responses in Human Skeletal Muscle.
Effect of Epigallocatechin Gallate Supplementation on Inflammation, Iron Status, and Metabolomic Profiles in Women With Obesity: A Pilot Randomized Controlled Trial.
Age at menopause and subjective cognitive symptoms predict digital cognitive outcomes at the gynecological Well-Woman visit.
Lac-Phe: An Exercise Hormone for Metabolic Regulation.
Puerarin extends lifespan and enhances the resistance to oxidative stress through AMPK/TFEB mediated autophagy in Caenorhabditis elegans.
Redox-sensitive coordination of mitochondrial quality control: Integrating ROS, NAD+, and Ca2+ signaling in disease.
Reprogramming brain bioenergetics in depression: an integrative framework linking creatine, branched-chain amino acids, and exercise to neuroplasticity, cognitive function, and depression-related outcomes.
Novel SIRT1 Up-regulator F1462 Attenuates Endothelial Cell Senescence and Vascular Aging by Promoting Mitochondrial Biogenesis via Activating the SIRT1/PGC-1α/TFAM Pathway.
SLC25A12 mitigates mitochondrial dysfunction in myoblast senescence, and alleviates cuproptosis-related changes under copper stress.
Sedative-hypnotic properties and mitochondrial effects of coenzyme Q2 in mice.
The GLP-1-Mitochondria Axis in Metabolic Aging.
Triclosan induces DNA damage in human ovarian granulosa cells via mitochondrial superoxide overproduction mediated by suppressed glutathione synthesis.
Azelaic Acid delays aging and prolongs lifespan via resisting oxidation stress mediated by IIS pathway coupling hsf-1 in C. elegans.

Gerontology. 2026 Aug 17. 1-21

Mitochondrial Dysfunction as a Central Hub of Aging: From Molecular Cascades to Inter-Organ Communication Networks.

Chaodong Han, Zilian Zhang, Yafeng Song.

: Background: Mitochondrial dysfunction serves as a fundamental driver of the aging process, precipitating progressive functional decline through complex molecular cascades. Summary: This review elucidates the core mechanisms underpinning this dysfunction, including reactive oxygen species (ROS)-induced redox imbalance, mitochondrial DNA (mtDNA) damage accumulation, impaired mitophagy, and metabolic reprogramming. Crucially, we examine how mitochondria act as signaling hubs for inter-organ crosstalk. Through the secretion of mitokines (e.g., FGF21, GDF15) and the release of damage-associated molecular patterns (DAMPs), dysfunctional mitochondria trigger chronic inflammation via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and NLRP3 inflammasome (NLRP3) pathways, actively driving systemic aging within the skeletal muscle-brain and adipose/liver-cardiovascular axes. Additionally, this paper synthesizes current therapeutic interventions, ranging from lifestyle modifications and nicotinamide adenine dinucleotide (NAD+) precursors to frontier technologies like mitochondrial transplantation and gene editing. Key Messages: While promising in animal models, clinical translation of these interventions is currently hindered by limited long-term safety data and evidence gaps. Therefore, mitochondria-targeted studies incorporating integrated multi-organ phenotyping are urgently required to establish robust strategies for extending human healthspan.

DOI: https://doi.org/10.1159/000553430
Hum Reprod Update. 2026 Aug 19. pii: dmag022. [Epub ahead of print]

The role of mitochondrial dysfunction and genetics in female infertility and premature ovarian insufficiency.

Brianna L Kline, Alison G Compton, Ann E Frazier, Svenja Pachernegg, Andrew H Sinclair, Katie L Ayers, Elena J Tucker.

   BACKGROUND: Female infertility occurs in ∼37% of infertile couples, while premature ovarian insufficiency (POI) impacts 1-3.7% of women under the age of 40. POI is clinically heterogeneous, with various genetic pathways associated with its pathogenesis. Mitochondrial diseases (MDs) are a broad group of clinically heterogeneous genetic conditions characterized by aberrantly functioning mitochondria. MDs have a disproportionate burden on organs and tissues with increased aerobic/energy demands, such as the heart, skeletal muscles, brain, and ovaries. The role of mitochondria in female fertility and ovarian reserve is increasingly being recognized.
OBJECTIVE AND RATIONALE: A comprehensive understanding of the role of mitochondria in the maintenance of female fertility is pertinent to better understanding female reproductive potential. In a world with increasing demand for assisted reproductive technologies (ART), due to a considerable rate of global infertility, there is a need to better understand the genes and pathways involved in female reproduction. This review summarizes, evaluates, and explores the current knowledge of mitochondria-associated genes and variants that are implicated in POI, including their function and dysfunction in female reproduction.
SEARCH METHODS: We searched articles in the PubMed database, containing the following key words: premature ovarian insufficiency, mitochondria, mitochondrial, premature ovarian failure, genetics, mitochondrial DNA, mtDNA, mitochondrial protein, infertility, premature menopause, mitochondrial donation, assisted reproductive technologies, electron transport chain, oxidative phosphorylation (OXPHOS), mitochondrial disease, oocyte, oogenesis, meiosis, in vitro fertilization, mitoribosome, Perrault syndrome, and ovarioleukodystrophy, in the English-language literature until March 2026.
OUTCOMES: Genetic variants that affect mitochondrial genes/proteins can negatively impact ovarian function. Various mitochondrial pathways are associated with female infertility, reflecting the broad sensitivity of ovarian reserve to mitochondrial dysfunction. Mitochondrial dysfunction and infertility can present in isolation or as part of a syndrome. Infertility in women may be the first clinical sign of a MD. Conversely, POI may be an underappreciated symptom of MDs.
WIDER IMPLICATIONS: This review draws attention to the fact that females with MDs should be monitored for POI so it can be detected early for prompt and appropriate therapeutic interventions, such as hormone replacement therapy. This is known to mitigate the risk of comorbidities such as cardiovascular and bone disease and will optimize long-term health outcomes. Of equal importance, our review highlights the potential for girls and women presenting with apparently 'isolated' POI to harbour pathogenic variants in MD-associated genes, therefore putting these individuals at risk of developing further clinical manifestations of MDs. We emphasize the need for surveillance in these cases for hearing loss, vision disturbance, cardiomyopathy, muscle weakness and neurodegeneration, depending on the genetic cause. Given that mitochondrial function is essential to female fertility, future therapies for mitochondria-associated infertility could involve mitochondrial supplementation to improve the mitochondrial fraction or mitochondrial donation to optimize the likelihood of reproductive success. Finally, we also discuss the current landscape of biomarkers as potential early diagnostic tools for POI. Whilst currently rudimentary in their clinical utility, the further development of early screening methods will be invaluable for the detection, diagnosis, and early intervention of POI.
REGISTRATION NUMBER: N/A.

Keywords:  POI; genetics; infertility; mitochondria; mitochondrial disease; premature ovarian insufficiency

DOI:  https://doi.org/10.1093/humupd/dmag022
bioRxiv. 2026 Aug 07. pii: 2026.08.06.743074. [Epub ahead of print]

17α-Estradiol Confers Limited Protection Against APOE4 Phenotypes in Middle-Aged Female Mice.

Cassandra J McGill, Amy Christensen, Sara Namvari, Max A Thorwald, Herbert Anson, Marc Vermulst, Caleb E Finch, Bérénice A Benayoun, Christian J Pike.

Longevity-promoting interventions represent a promising strategy to mitigate brain aging and reduce Alzheimer's disease (AD) risk. The NIA Interventions Testing Program identified the weak estrogen 17α-estradiol (17αE2) as a compound that extends healthspan and lifespan in mice, with effects observed primarily in males. Our recent work demonstrated that 17αE2 healthspan benefits were modulated by human apolipoprotein E ( APOE ) genotype such that aging phenotypes were improved more strongly in middle-aged male mice with targeted-replacement of the AD-associated APOE4 allele compared to APOE3 , the risk neutral and most common APOE allele. Here, we tested whether APOE -dependent, AD-relevant benefits of 17αE2 observed in males extend to females. Specifically, we treated 12-month-old APOE3 and APOE4 targeted-replacement female mice for 6 months with chow containing 0 or 14.4ppm 17αE2. We find that relative to APOE3 , APOE4 genotype largely exhibits more robust systemic phenotypes associated with aging, including increased adiposity, impaired glucose tolerance, and reduced energy expenditure. Further, we observe that treatment with 17αE2 yields modest improvements in some outcomes, including decreased adiposity and increased lean mass, glucose tolerance, and energy expenditure, though significant benefits are found only in APOE4 females. In the CNS, we observed mixed effects of APOE genotype on behavioral performance and indices of brain aging, with APOE4 females performing worse in the Barnes Maze and having higher levels of the AD-related peptide soluble β-amyloid, but no APOE genotype differences in cortical lipid raft oxidative damage. In contrast to its systemic effects, 17αE2 did not significantly improve neural outcomes in APOE3 or APOE4 females. These findings address the impact of biological sex on established protective effects of a longevity-promoting intervention against APOE4 phenotypes, which have significant relevance to the prevention of age-related conditions including metabolic dysfunction, cognitive impairment and vulnerability to AD.

DOI: https://doi.org/10.64898/2026.08.06.743074
Int J Sports Med. 2026 Aug 19.

Cell-Free Circulating Mitochondrial DNA: A Biomarker of Physiological Stress and Adaptation in Athletes.

Arpan Chattopadhyay, Patrick Diel, Hemanth Naick B.

Abstract: Circulating cell-free mitochondrial DNA has recently gained attention as a sensitive biomarker of physiological stress and adaptation in athletes. Intense exercise challenges mitochondrial function and can lead to the release of circulating cell-free mitochondrial DNA into the circulation, where it acts as a mitochondrial damage-associated molecular pattern. These fragments, recognized by the innate immune system due to their bacterial-like CpG motifs, trigger inflammatory responses and reflect cellular strain. Acute bouts of high-intensity exercise, mechanical stress, or trauma are associated with sharp increases in circulating cell-free mitochondrial DNA levels, while consistent training and regular recovery help maintain lower baseline concentrations, suggesting a role in adaptive regulation. Elevated circulating cell-free mitochondrial DNA levels in athletes have been linked to impaired recovery, increased inflammatory burden, and potential overtraining, whereas controlled exercise appears to facilitate its clearance and contribute to systemic resilience. Beyond physical performance, emerging evidence suggests that circulating cell-free mitochondrial DNA is also linked to psychobiological stress, offering an insight into both the physical and mental demands placed on athletes. Monitoring circulating cell-free mitochondrial DNA dynamics alongside traditional physiological measures such as cortisol, maximal oxygen uptake, and haematological markers could therefore provide a more comprehensive assessment of training load, recovery status, and susceptibility to stress-related disorders. As sports science advances toward precision monitoring, circulating cell-free mitochondrial DNA represents a promising molecular tool for guiding individualized training programs, preventing overtraining, and safeguarding long-term athlete health.

DOI: https://doi.org/10.1055/a-2929-9682
Aging Cell. 2026 Sep;25(9): e70678

Aged Mitochondrial DNA Is Associated With Aberrant Acute Exercise-Induced Redox Responses in Human Skeletal Muscle.

Bradley A Ruple, Nicholas A Carlini, Jason S Kofoed, Helya Rostamkhani, Brady E Hanson, Jesse C Craig, Shelby C Osburn, Allison M Manuel, Paul A Stewart, Jonathan Wanagat, Ryan M Broxterman, Joel D Trinity.

  Redox imbalances and mitochondrial dysfunction are key contributors to age-related declines in skeletal muscle and may contribute to impaired exercise responsiveness. Here, we investigated the influence of aging on skeletal muscle redox at rest and in response to acute exercise, examining how mitochondrial quality and quantity relate to skeletal muscle redox status. Skeletal muscle biopsies were obtained from 12 young (22 ± 4 years) and 10 older adults (66 ± 7 years) before and immediately after 60-min of high-intensity knee-extension exercise. We assessed mitochondrial respiration, mitochondrial DNA (mtDNA) copy number and deletion mutation frequency at baseline, while skeletal muscle redox proteomics was performed on pre- and post-exercise biopsies in a subset of participants. Mitochondrial respiration was preserved with age (max respiration, p = 0.123). However, the older adults had a lower mtDNA copy number (p = 0.046) and higher mtDNA deletion frequency (p = 0.001), with widespread remodeling of the skeletal muscle redox proteome, including altered thiol occupancy of proteins involved in metabolism, immune function, and extracellular matrix organization. In response to exercise, young skeletal muscle exhibited predominantly reversible peptide reductions, whereas preferential oxidation of mitochondrial antioxidant proteins, including PRDX3, occurred in older muscle. Both mtDNA deletion frequency and mitochondrial respiration were strongly associated with exercise-induced redox modifications in mitochondrial proteins. These findings suggest that aging alters both the regulation and resolution of exercise-induced redox signaling, with mitochondrial genomic instability and respiration shaping redox responsiveness.

Keywords:  aging; exercise; mitochondrial DNA; oxidative stress; redox proteomics

DOI:  https://doi.org/10.1111/acel.70678
Mol Nutr Food Res. 2026 Aug;70(16): e70575

Effect of Epigallocatechin Gallate Supplementation on Inflammation, Iron Status, and Metabolomic Profiles in Women With Obesity: A Pilot Randomized Controlled Trial.

Sixtus Aguree, Kedir N Turi, Alexandra R Handt, Marian Kohut, Manju B Reddy.

  Obesity in women of reproductive age is often associated with low-grade inflammation and functional iron deficiency. Epigallocatechin gallate (EGCG), a major green tea catechin, has antioxidant, anti-inflammatory, and metabolic-regulating properties but may also interfere with iron absorption. This randomized, double-blind, placebo-controlled pilot study evaluated the effects of EGCG on lipid profile, inflammation, iron status, and plasma metabolomics in women with obesity. Seventeen participants (BMI ≥30 kg/m2; age 20-44 years) received 400 mg/day EGCG (green tea extract: 98% polyphenols, 60% catechins, ∼50% EGCG) or placebo for eight weeks. Outcomes included serum lipids, inflammatory markers (CRP, IL-6, TNF-α, IL-10), iron indices (ferritin, hepcidin, serum iron, transferrin saturation), glucose, and metabolomics. No between-group difference remained significant after correction for multiple comparisons. Total cholesterol (β = -10.9 mg/dL; p = 0.16) and LDL-C (β = -9.7 mg/dL; p = 0.16) showed decreases, and IL-6 the largest, though nonsignificant, reduction (p = 0.09); other cytokines and glucose were unchanged. Metabolomics identified 29 nominally differential metabolites enriched in lipid metabolism, plasmalogen biosynthesis, and mitochondrial β-oxidation, none surviving FDR correction. Iron status was stable. These findings suggest metabolic effects of EGCG and support short-term safety at 400 mg/day. Larger, longer trials with targeted metabolomics are warranted.

Keywords:  epigallocatechin gallate; inflammation; iron homeostasis; lipid metabolism; metabolomics; obesity

DOI:  https://doi.org/10.1002/mnfr.70575
J Clin Exp Neuropsychol. 2026 Aug 19. 1-12

Age at menopause and subjective cognitive symptoms predict digital cognitive outcomes at the gynecological Well-Woman visit.

Teresa Facchetti, Jillian L Joyce, Sandra Rizer, Sarah E Tom, Karen Marder, Silvia Chapman, Mary L Rosser, Stephanie Cosentino.

   INTRODUCTION: Women are at increased risk for Alzheimer's Disease (AD). Growing evidence suggests that the menopausal transition may represent a vulnerable window for development of AD-related pathology. Yet, women are diagnosed with AD later than men. Conducting routine cognitive screenings and integrating information about both cognitive symptoms and age at menopause may help address sex-based disparities in detection and prevention. This study investigated whether subjective cognitive symptoms, in combination with age at menopause, were associated with performance on a digital cognitive task in postmenopausal women.
METHODS: 183 postmenopausal women (mean age = 63.8, range = 45-85) were recruited after their Well-Woman visit. Participants completed the Screener for Cognitive Problems in Everyday Life (SCoPE) to assess subjective cognitive symptoms, followed by a sensitive measure of objective cognition: the Linus Health Digital Clock and Recall (DCR™). Information was also collected on age at menopause. We examined associations of subjective cognitive symptoms and age at menopause with digital cognitive performance, adjusting for age, education and depression. Model fit was evaluated using adjusted R2, AIC, and BIC.
RESULTS: 48.1% of women reported one or more cognitive symptoms on the SCoPE. On objective testing, 73.2% scored in the normal range, 20.8% in the borderline range, and 6.0% in the impaired range. SCoPE total score was negatively associated with objective cognitive performance in adjusted models (B = -.12, p = .03). Age at menopause showed a significant quadratic association with cognitive performance (B = -0.006, p<.001). SCoPE total was not associated with DCR subtests, while age at menopause predicted both Delayed Recall and Clock Drawing.
CONCLUSION: Subjective cognitive symptoms and age at menopause were associated with lower performance on a sensitive, objective cognitive test. Findings support routine cognitive screening and suggest that subjective cognitive symptoms as well as age at menopause are associated with cognitive function.

Keywords:  Alzheimer’s Disease; Memory screening; Well-Woman visit; cognition; early detection; subjective cognitive decline

DOI:  https://doi.org/10.1080/13803395.2026.2707992
Annu Rev Nutr. 2026 Aug;46(1): 153-175

Lac-Phe: An Exercise Hormone for Metabolic Regulation.

Qingzhuo Liu, Yong Xu.

  N-Lactoyl-phenylalanine (Lac-Phe), a conserved exercise-induced metabolite that rises rapidly in circulation, has emerged as a key molecular mediator linking fundamental metabolism to translational medicine. In this review, we elaborate recent findings that define a two-step framework for Lac-Phe biosynthesis and excretion. Functional studies show that Lac-Phe exerts broad metabolic benefits and should be regarded as a bioactive molecule rather than a passive by-product of intermediary metabolism. Furthermore, we review the neural mechanisms through which Lac-Phe conveys peripheral metabolic cues to central circuits regulating appetite and energy balance. Beyond the role of Lac-Phe in energy balance, alterations in Lac-Phe concentrations are associated with disease pathogenesis and progression, underscoring its potential as both a biomarker and a therapeutic agent. Collectively, these advances position Lac-Phe at the intersection of exercise physiology, metabolism, and disease and thus highlight its potential to integrate metabolic and physiological health.

Keywords:  CNDP2; N-lactoyl-phenylalanine; clinical applications; energy balance; exercise; hypothalamic neural circuits

DOI:  https://doi.org/10.1146/annurev-nutr-061824-054717
Mech Ageing Dev. 2026 Aug 21. pii: S0047-6374(26)00090-4. [Epub ahead of print] 112238

Puerarin extends lifespan and enhances the resistance to oxidative stress through AMPK/TFEB mediated autophagy in Caenorhabditis elegans.

Lingjie Meng, Yang Liu, Xiaocong Li, Xin Xiao, Xinyi Du, Fang Liu, Yi Xiao.

  As the aging population increases, exploring effective strategies to delay aging and promote healthy longevity has become a crucial topic in the life sciences. Puerarin (PUE) is a natural isoflavone derivative derived from Pueraria lobata, a plant widely recognized for its dual role as both a food and a medicinal herb. While PUE is known for its diverse pharmacological properties, its role in aging regulation and the associated molecular mechanisms are not yet fully elucidated. In this study, we found that PUE markedly extends the healthy lifespan of Caenorhabditis elegans and mitigates aging-related phenotypes, including lipofuscin accumulation and decreased locomotor capacity. Through genetic screening and functional validation, we demonstrated that PUE facilitates the nuclear translocation of the transcription factor HLH-30 (the mammalian homolog of TFEB) in an AMPK-dependent manner, thereby regulating autophagy. Importantly, this autophagic response was essential for the lifespan-extending effects of PUE. Additionally, PUE enhanced the oxidative stress resistance of C. elegans via the AMPK-TFEB signaling pathway, an effect characterized by reduced reactive oxygen species (ROS) accumulation and increased activities of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione (GSH). The findings establish a mechanistic rationale for applying PUE in aging delay and age-related disease prevention and underscore the potential significance of medicinal food plants in developing anti-aging strategies.

Keywords:  AMPK/TFEB signaling pathway; Autophagy; Lifespan; Oxidative stress; Puerarin

DOI:  https://doi.org/10.1016/j.mad.2026.112238
Life Sci. 2026 Aug 20. pii: S0024-3205(26)00451-0. [Epub ahead of print]403 124642

Redox-sensitive coordination of mitochondrial quality control: Integrating ROS, NAD+, and Ca2+ signaling in disease.

Ilitch A Marcondes-de-Castro, Thamyres Alves Sales, Thatiany Souza Marinho, Marcia Barbosa Aguila, Carlos A Mandarim-de-Lacerda.

  Mitochondrial quality control (QC) preserves cellular homeostasis by coordinating mitochondrial structure, turnover, and bioenergetic function. Rather than operating through isolated pathways, QC is increasingly recognized as an integrated, redox-sensitive network in which reactive oxygen species (ROS), nicotinamide adenine dinucleotide (NAD+), and calcium (Ca2+) signaling regulate mitochondrial dynamics, mitophagy, biogenesis, and, ultimately, cell fate. In this narrative review, we propose a hierarchical framework in which these signaling systems function as interconnected sensors and transducers that determine whether mitochondria undergo repair, adaptive remodeling, or elimination. Under physiological conditions, controlled ROS production, adequate NAD+ availability, and tightly regulated Ca2+ flux promote a balanced mitochondrial fusion and fission, efficient mitophagic turnover, and mitochondrial biogenesis, thereby preserving bioenergetic competence and metabolic flexibility. Mitochondria-associated membranes (MAMs) emerge as key spatial platforms that integrate redox signaling, Ca2+ transfer, and lipid exchange, synchronizing communication between the endoplasmic reticulum and mitochondria. Conversely, persistent redox imbalance, characterized by excessive ROS, NAD+ depletion, and Ca2+ dysregulation, disrupts the coordination of QC pathways, resulting in mitochondrial fragmentation, defective turnover, impaired biogenesis, bioenergetic failure, and activation of apoptotic signaling. We critically discuss the mechanistic interplay among these pathways across metabolic disorders, cardiovascular disease, neurodegeneration, cancer, and aging, highlighting context-dependent adaptive and maladaptive responses. Finally, we identify unresolved questions regarding the spatiotemporal integration of redox signals, tissue-specific regulation of mitochondrial QC, and therapeutic targeting of network-level regulatory nodes. This framework provides a systems-level perspective for understanding how coordinated redox signaling governs mitochondrial adaptation and contributes to disease pathogenesis.

Keywords:  Mitochondria-associated membranes; Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy; Redox signaling

DOI:  https://doi.org/10.1016/j.lfs.2026.124642
Front Psychiatry. 2026 ;17 1830803

Reprogramming brain bioenergetics in depression: an integrative framework linking creatine, branched-chain amino acids, and exercise to neuroplasticity, cognitive function, and depression-related outcomes.

Xiaoqin Xu, Li Liu.

  Depression represents a multifaceted neuropsychiatric disorder distinguished by disruptions in cerebral energy metabolism, neurotransmitter communication, neuroplasticity, and cognitive processes. An increasing body of literature indicates that integrative non-pharmacological interventions aimed at metabolic and neurochemical pathways may present promising adjunctive strategies for ameliorating depressive manifestations and concomitant cognitive impairments. This review explores the prospective combined effects of creatine supplementation, branched-chain amino acids (BCAAs), and physical exercise as a multimodal bioenergetic intervention for the management of depression. Creatine is pivotal in maintaining neuronal energy equilibrium via the phosphocreatine system, thereby facilitating mitochondrial functionality and adenosine triphosphate availability within neural cells. BCAAs may influence central fatigue and exercise performance through competitive inhibition of tryptophan transport across the blood-brain barrier. Importantly, this mechanism primarily reflects acute exercise-related serotonergic responses associated with central fatigue and should not be considered mechanistically equivalent to the chronic serotonergic dysfunction observed in major depressive disorder. Accordingly, within the context of depression, BCAAs are discussed as indirect modulators of mental health outcomes through their effects on fatigue perception, exercise tolerance, and adherence to physical activity, rather than as direct serotonergic antidepressant interventions. Concurrently, consistent engagement in physical exercise activates critical neuroplasticity-associated signaling pathways, which are instrumental in promoting hippocampal neurogenesis and enhancing stress resilience. Emerging empirical evidence derived from both experimental and clinical investigations suggests that the combined application of these interventions may exert complementary influences on brain bioenergetics, neuroplasticity, exercise capacity, and cognitive function. Collectively, this integrative paradigm highlights the potential of creatine supplementation, BCAAs, and physical exercise to support depression-related outcomes through distinct yet complementary mechanisms involving bioenergetic regulation, enhanced exercise capacity, neuroplastic adaptations, and improved cognitive and emotional functioning.

Keywords:  branched-chain amino acids; cognitive function; creatine; depression; exercise; neuroplasticity; serotonin signaling

DOI:  https://doi.org/10.3389/fpsyt.2026.1830803
Eur J Pharmacol. 2026 Aug 20. pii: S0014-2999(26)00755-7. [Epub ahead of print] 179273

Novel SIRT1 Up-regulator F1462 Attenuates Endothelial Cell Senescence and Vascular Aging by Promoting Mitochondrial Biogenesis via Activating the SIRT1/PGC-1α/TFAM Pathway.

Shunwang Li, Xuan Zuo, Chao Liu, Jiangxue Han, Yuhao Zhang, Jing Zhang, Jingshuai Wu, Guijun Yang, Ren Sheng, Jingrui Wang, Xinwei Wei, Weilian Jiang, Chuanjia Ju, Yuyan Zhang, Lijuan Lei, Yanni Xu, Shuyi Si.

  Vascular aging constitutes a critical driver of age-related cardiovascular diseases (CVDs). Sirtuin 1 (SIRT1) is well established to confer protection against aging and aging-associated pathologies. In the present study, we identified and elucidated the protective effects and mechanisms of F1462, a novel SIRT1 up-regulator, against vascular endothelial cell (EC) senescence and vascular aging. Using a doxorubicin (DOX)-induced EC senescence model, we demonstrated that F1462 dose-dependently suppressed the senescence markers p53 and p21 and lowered senescence-associated secretory phenotype (SASP)-related inflammatory factors. F1462 improved mitochondrial function by restoring mitochondrial membrane potential (MMP), diminishing the generation of total reactive oxygen species (ROS) and mitochondrial reactive oxygen species (mtROS) production, and evaluating ATP production. The beneficial effects of F1462 were further validated in an H2O2-induced EC senescence model. Mechanistically, F1462 facilitated mitochondrial biogenesis by activating the SIRT1/PGC-1α/TFAM signaling pathway. SIRT1 knockdown abrogated these protective effects against cellular senescence and mitochondrial dysfunction in the DOX-induced EC senescence model. Notably, in naturally aged mice, F1462 reduced plasma SASP inflammatory factors and vascular senescence-associated β-galactosidase (SA-β-Gal) activity, and mitigated aging-triggered vascular wall thickening. In conclusion, F1462 alleviates vascular EC senescence and vascular aging by boosting mitochondrial biogenesis through activation of the SIRT1/PGC-1α/TFAM axis, therefore representing a promosing candidate for the treatment of vascular aging and associated CVDs.

Keywords:  F1462; SIRT1; endothelial cells; mitochondrial biogenesis; vascular aging

DOI:  https://doi.org/10.1016/j.ejphar.2026.179273
Biol Direct. 2026 Aug 03. pii: 150. [Epub ahead of print]21(1):

SLC25A12 mitigates mitochondrial dysfunction in myoblast senescence, and alleviates cuproptosis-related changes under copper stress.

Shengwei Wang, Weigen Wu, Hua Yin, Qiushuo Chen, Ling Zhang, Wen He.

   BACKGROUND: Sarcopenia is an age-related muscle wasting condition that currently lacks specific diagnostic biomarkers and effective treatments. This study aimed to identify mitochondria-related biomarkers for sarcopenia via integrated multi-omics.
METHODS: Human transcriptomic datasets and machine learning algorithms were integrated to screen core mitochondria-related biomarkers for sarcopenia. In vivo validation was performed utilizing 24-month-old naturally aging mice exhibiting sarcopenia features. In vitro, SLC25A12 was either overexpressed or silenced in C2C12 myoblasts subjected to D-galactose-induced senescence or copper stress. Pathophysiological changes and molecular mechanisms were subsequently evaluated via immunofluorescence, mitochondrial functional assays, and Western blotting. Additionally, single-cell RNA sequencing combined with a Geneformer model was employed in MuSCs for in silico perturbation analysis.
RESULTS: Transcriptomic and machine learning analyses identified SLC25A12 as a core mitochondria-related gene, exhibiting consistent downregulation in both human sarcopenia cohorts and 24-month-old aging mice. In vitro, SLC25A12 overexpression in C2C12 myoblasts significantly ameliorated senescence induced by D-galactose and preserved mitochondrial function, highlighted by increased EdU incorporation and restored membrane potential. Furthermore, under copper stress, elevated SLC25A12 levels effectively alleviated cuproptosis-related alterations, including restricting mitochondrial copper overload, suppressing DLAT oligomerization, and partially restoring impaired EdU incorporation. Conversely, SLC25A12 knockdown consistently aggravated these phenotypes in both models. Notably, in silico Geneformer-based perturbation of SLC25A12 in MuSCs predicted its regulatory roles in cellular senescence, mitochondrial function, and copper homeostasis. In vitro experiments further demonstrated that SLC25A12 overexpression partially restored suppressed PI3K/AKT signaling under senescent stress conditions.
CONCLUSION: SLC25A12 expression ameliorates myoblast senescence and mitochondrial dysfunction, while also attenuating cuproptosis-related changes under copper stress. SLC25A12 knockdown exacerbates these phenotypes. Taken together, SLC25A12 represents a potential regulator and therapeutic target for skeletal muscle aging.

Keywords:  Aging; Cuproptosis; Mitochondrial dysfunction; SLC25A12; Sarcopenia

DOI:  https://doi.org/10.1186/s13062-026-00918-w
Curr Mol Pharmacol. 2025 ;18(1): 100-107

Sedative-hypnotic properties and mitochondrial effects of coenzyme Q2 in mice.

Haeun Lim, Rong Lu, Sahdev N Patel, Sebastian Zinn, Paul S García, Richard J Levy.

   Background: Anesthetics are fascinating drugs capable of inducing reversible unconsciousness. Functional targets of these agents exist within mitochondria and disruption of bioenergetic capacity plays a role in mediating the anesthetic response. Recently, ubiquinone-5 (coenzyme Q1)(Ub5 or CoQ1), a short-chain coenzyme Q (CoQ) analog with a single isoprene unit, was identified as a novel anesthetic with a mitochondrial mechanism. Benzoquinones share an identical head group yet differ in the length of their isoprenoid tail. It is unknown if other CoQ analogs exhibit anesthetic properties or how side-chain length affects their activity. Here, we hypothesized that CoQ2, an analog with two isoprene tail units, would act as a sedative-hypnotic and that its mitochondrial biological activity would differ from Ub5 (CoQ1).
Methods: Behavioral phenotype was assessed in mice using behavioral and neurophysiological approaches. We measured activity within isolated mitochondria using polarography and spectrophotometry and attempted to identify source of proton leak using pharmacological inhibitors.
Results: CoQ2 induced brief and reversible brain quiescence shortly after injection and caused a precipitous decline in the mitochondrial membrane potential due to excessive mitochondrial proton leak combined with electron transport chain inhibition. Unlike Ub5 (CoQ1), however, there was a latency to onset of CoQ2-induced hypnosis, effective CoQ2 doses were relatively higher, and duration of CoQ2-mediated unconsciousness was relatively longer than that previously reported for Ub5 (CoQ1). Furthermore, the source of proton leak differed between analogs.
Conclusions: The comparable anesthetic effects likely relate to the benzoquinone head group shared between molecules while the disparities are likely due to the length of the isoprenoid tail.

Keywords:  Anesthesia; Benzoquinone; Coenzyme Q; Membrane potential; Mitochondria; Proton leak

DOI:  https://doi.org/10.1016/j.cmp.2025.12.001
Aging Cell. 2026 Aug;25(8): e70676

The GLP-1-Mitochondria Axis in Metabolic Aging.

Renin Chang, Andy P Tsai, Boyang Wang, Chia-Jung Li.

  Metabolic aging underlies a cluster of chronic conditions-type 2 diabetes, cardiovascular disease, sarcopenia, and neurodegeneration-that account for a substantial share of global morbidity and mortality. A common feature is progressive mitochondrial dysfunction: impaired bioenergetics, disrupted quality control, and loss of metabolic resilience. Reduced mitochondrial DNA copy number in peripheral blood leukocytes is associated with cardiometabolic disease and mortality, but pre-analytical variability, dependence on blood-cell composition, and uncertain relationship to tissue-level function mean it should be regarded as a candidate risk-associated biomarker rather than a validated measure of mitochondrial integrity. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), developed for glycemic control, engage pathways implicated in mitochondrial biogenesis, dynamics, and mitophagy; whether these effects reflect direct receptor signaling, indirect consequences of weight loss, or secondary mediators such as interleukin-6 remains debated and appears tissue-dependent. In SELECT, semaglutide reduced major adverse cardiovascular events by 20% in obesity without diabetes, and a 2025 multi-omic study in aged male mice found GLP-1 RA treatment attenuated age-associated molecular signatures despite only modest changes in food intake and body weight. No trial, however, has incorporated a prespecified mitochondrial endpoint, human mechanistic evidence remains limited, and access to these therapies remains uneven worldwide. Here we synthesize mechanistic, preclinical, and clinical evidence for a proposed GLP-1-mitochondria axis, classify this evidence by receptor dependence and translational stage, distinguish disease-specific treatment effects from evidence for aging modification, examine four major controversies, and outline a research and policy agenda for responsible, evidence-graded development of GLP-1-based geroscience interventions.

Keywords:  GLP‐1 receptor agonists; geroscience; healthy aging; metabolic aging; mitochondrial dysfunction; mitochondrial resilience; population health

DOI:  https://doi.org/10.1111/acel.70676
Chem Biol Interact. 2026 Aug 21. pii: S0009-2797(26)00419-9. [Epub ahead of print] 112311

Triclosan induces DNA damage in human ovarian granulosa cells via mitochondrial superoxide overproduction mediated by suppressed glutathione synthesis.

Meng Yang, Yuping Xiao, Mingquan Huang, Shuang Liu, Guangrui Pan.

  Triclosan (TCS) is a broad-spectrum antimicrobial agent that has raised public health concerns due to its continuous environmental release and human exposure. Previous studies suggest that TCS may disrupt endocrine function. Nonetheless, the toxicological effects on the female reproductive system, notably on ovarian granulosa cells, and the underlying pathways remain poorly understood. This study was designed to examine the toxic effects of TCS on human granulosa cells and the related mechanisms. To this end, human granulosa cell lines (KGN and SVOG) were treated in vitro with varying doses of TCS. The results demonstrated that TCS exposure led to marked cytotoxicity and DNA damage in a dose-dependent manner. Transcriptomic profiling showed that TCS markedly affected pathways associated with mitochondrial respiratory chain function and DNA repair mechanisms within granulosa cells. Subsequent mechanistic studies revealed that TCS led to mitochondrial dysfunction, as evidenced by reduced activity of mitochondrial respiratory chain complex I and a marked increase in mitochondrial ROS levels. Application of the mitochondria-targeted antioxidant MitoTEMPOL significantly alleviated the ROS accumulation and DNA damage induced by TCS. Specifically, we found that TCS exposure suppressed the synthesis of glutathione (GSH), a key component of the endogenous antioxidant defense system. The decline in GSH synthesis was further confirmed to be an upstream initiating factor for TCS-induced mitochondrial ROS production and DNA damage in granulosa cells, as evidenced by glutathione monoethyl ester (GSH-MEE) pretreatment. These findings reveal a previously unrecognized molecular mechanism by which TCS impairs ovarian reserve function, thereby providing important theoretical insights for assessing the reproductive toxicity risk of TCS and suggesting that antioxidants targeting GSH and mitochondria may represent a potential intervention strategy.

Keywords:  DNA damage; Triclosan; glutathione synthesis; granulosa cells; mitochondrial superoxide; oxidative stress

DOI:  https://doi.org/10.1016/j.cbi.2026.112311
Biosci Biotechnol Biochem. 2026 Aug 19. pii: zbag127. [Epub ahead of print]

Azelaic Acid delays aging and prolongs lifespan via resisting oxidation stress mediated by IIS pathway coupling hsf-1 in C. elegans.

Yang Chen, Liangliang Wang, Zixian Zhu, Beibei Pan, Juan Bai.

  Azelaic acid (AzA), an antioxidant and anti-inflammatory compound from cereals used in food preservatives and cosmetics, was investigated for anti-aging effects in Caenorhabditis elegans. AzA improved locomotive activities and muscle morphology during aging, extended lifespan under both normal and oxidative stress conditions, and reduced paralysis in neurodegenerative models. It decreased reactive oxygen species levels and enhanced superoxide dismutase (SOD) activity and SOD-3 protein expression. Quantitative real-time PCR (qRT-PCR) analysis revealed that AzA differentially regulated oxidative stress-related genes including daf-2, daf-16, skn-1, and hsf-1 under normal and oxidative stress conditions. Mechanistically, the lifespan extension conferred by AzA under oxidative stress was abolished in daf-16(mu86), daf-2(e1370), and hsf-1(sy441) mutants, indicating that these genes are essential for AzA-mediated anti-aging effects. These findings suggest that azelaic acid is a potential anti-aging candidate.

Keywords:   Caenorhabditis elegans ; Azelaic Acid; IIS pathway; aging; oxidative stress

DOI:  https://doi.org/10.1093/bbb/zbag127