bims-mistre 2026-10-18 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–10–18
thirty-one papers selected by
Ellen Siobhan Mitchell, MitoQ

From stress cytokine to drug target: The translational landscape of growth differentiation factor 15.
Harnessing cGAS-STING in neurodegeneration: From mitochondrial DNA leakage and microglial reactivity to species-specific translational barriers.
The cGAS-STING signaling axis in Type 2 diabetes-associated cognitive decline: from mitochondrial DNA sensing to neurodegeneration.
Mitochondrial-derived peptides in female reproduction: Emerging regulators of oocyte competence and novel therapeutic opportunities for infertility.
Ergothioneine Mediated Neuroprotective Effects in the Nervous System.
Sex-Specific Early Life Corticosterone Stress-Coping Capacity Is Linked to Mitochondrial Content and Telomere Maintenance.
Dopamine-induced mitochondrial dysfunction activates cGAS-sTING to drive IL-6 secretion in macrophages.
Spermidine protects mitochondria against amyloid-β oligomers.
GDF15 Induces Weight Loss with Diet- and Age-Dependent Metabolic Effects Across Tissues in Mice.
Comparative lifespan trajectories of brain energy metabolism in human and macaque.
Mitochondrial dysfunction in Alzheimer's disease: mechanisms, pathogenic interplay, and therapeutic opportunities.
Redox resilience in skeletal muscle aging: cellular adaptations and exercise-mediated homeostasis.
Mitochondrial Psychobiology.
Topical application of urolithin A activates mitophagy and enhances mitochondrial function to promote skin longevity.
Association of mitochondrial copy number and heteroplasmy with cognitive function in the ACCORD trial.
The Human Ovary Exhibits Dynamic Molecular Remodeling in the Decades Post-Menopause.
A Randomized Clinical Trial: Daily Photoprotection With a Combined Sunscreen-Antioxidant Formulation Preserves Mitochondrial DNA Integrity in Human Facial Skin In Vivo.
The Effects of Topical and Oral Creatine on Skin Firmness and Resilience: A Review.
Resilience and vulnerability in the midbrain dopamine system during aging.
Childhood trauma in women with HIV is associated with increased mitochondrial respiration despite reduced mitochondrial DNA copy number.
Association between Gompertz law-based biological age (GOLD BioAge) and incident mild cognitive impairment: Modifying role of social activeness.
Four-week supplementation with a blackcurrant formulation enhances cognitive performance, reduces mental fatigue and modulates peripheral monoamine metabolism in older adults: a randomized, double-blind, placebo-controlled, crossover study.
Interventions with mitochondrial-related effects in older adults with type 2 diabetes: Protocol for a systematic review with conditional network meta-analysis.
Aging rate indicators and the search for anti-aging drugs.
Mitofusin-2 (MFN2) is a critical regulator of metabolic homeostasis in neuronal cells: A metabolomic and proteomic study.
Astaxanthin-rich extract supplementation counteracts cardiac oxidative stress in a rodent model of diet-induced Metabolic Syndrome.
Nicotinamide mononucleotide supports the development of bovine embryo through enhancement of mitochondrial function in morula.
Load and breath-hold: impact of 7-day creatine monohydrate loading on breath-hold exercise performance - a double-blind randomized controlled trial.
Influence of a full-spectrum aqueous extract of black cardamom (Amomum subulatum Roxb.) fruits on focus/alertness and executive function: a randomized, double-blind, placebo-and active- controlled, 14-day comparative study in healthy working professionals.
Turning back the ageing clock? Brain age in neuroprotective and clinical interventions.
Mitochondrial stress induces transcription of cytosolic and mitochondrial protein synthesis components via NHR-180.

J Pharmacol Exp Ther. 2026 Sep 28. pii: S0022-3565(26)01236-X. [Epub ahead of print]393(11): 105036

From stress cytokine to drug target: The translational landscape of growth differentiation factor 15.

Nicholas R Najjar, Bart C De Jonghe, Matthew R Hayes, Robert P Doyle.

  Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine that translates cellular injury, metabolic imbalance, and disease burden into systemic physiological responses. Discovery of its hindbrain-restricted receptor, glial cell line-derived neurotrophic factor family receptor α-like (GFRAL) and cosignaling partner rearranged during transfection (RET), established a dedicated neuroendocrine axis (GDF15-GFRAL-RET) linking stress to appetite suppression, nausea, and autonomic effects on energy expenditure. Initially regarded as a passive disease biomarker, GDF15 is now recognized as an active mediator in cancer-related anorexia-cachexia syndrome, chemotherapy-induced nausea and vomiting, obesity, aging, cardiovascular disease, hepatic, renal, gastrointestinal diseases, neurodegeneration, eating disorders, and hyperemesis gravidarum. This expanding biology has driven parallel development of GFRAL agonists and antagonists, as well as approaches to bind and eliminate circulating GDF15 in the treatment of illness behaviors associated with these numerous disease states. Here we review GDF15 biology and signaling from a medicinal chemistry perspective, examining reported structure-activity relationship-guided drug discovery across biologics and small molecules, including patents and ongoing clinical trials targeting the GDF15-GFRAL-RET axis. SIGNIFICANCE STATEMENT: Growth differentiation factor 15 (GDF15) is a stress-induced cytokine that signals through the hindbrain-restricted GFRAL-RET receptor complex to regulate appetite, nausea, and energy balance. This review highlights advances in understanding GDF15 biology, its role in disease, and synthesizes medicinal chemistry efforts targeting this pathway. By integrating structure-activity relationships, biologics, and small molecule approaches, this study outlines therapeutic strategies and translational challenges in modulating the GDF15-GFRAL-RET axis.

Keywords:  Agonists; Antagonists; Drug development; GDNF family receptor α-like; Growth differentiation factor 15; Rearranged during transfection

DOI:  https://doi.org/10.1016/j.jpet.2026.105036
Cytokine Growth Factor Rev. 2026 Oct 13. pii: S1359-6101(26)00084-5. [Epub ahead of print]92 101537

Harnessing cGAS-STING in neurodegeneration: From mitochondrial DNA leakage and microglial reactivity to species-specific translational barriers.

Mingfang Wang, Jierong Li, Xuanfang Wang, Xueting Chai, Jinghao Luo, Yingqi Zhang, Xuhong Chang, Yingbiao Sun, Hui Wang.

  The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, a cornerstone of innate immunity, has emerged as a critical driver of sterile neuroinflammation in the aging brain. Age-related decline in mitochondrial quality control, coupled with nuclear and lysosomal erosion, fosters the aberrant accumulation of cytosolic self-DNA, establishing a permissive environment for chronic cGAS-STING activation. This review synthesizes recent breakthroughs elucidating how major neurodegenerative diseases-Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease-converge on this pathway through distinct, disease-specific triggers, ranging from PINK1/Parkin deficiency-driven mitochondrial DNA leakage to TDP-43 proteinopathy-associated retrotransposon de-repression. Critically, we evaluate the translational landscape, highlighting the profound challenge posed by species-specific pharmacology, as exemplified by the failure of the covalent inhibitor H-151 to engage human STING. We argue that the future of therapeutic intervention lies not in wholesale pathway ablation, but in nuanced, context-dependent fine-tuning that disentangles its detrimental chronic effects from its indispensable homeostatic functions. This review positions the cGAS-STING axis as a promising yet delicate frontier for combating age-related neurodegeneration.

Keywords:  Aging; CGAS–STING; Innate immunity; Neuroinflammation

DOI:  https://doi.org/10.1016/j.cytogfr.2026.101537
Acta Diabetol. 2026 Oct 12.

The cGAS-STING signaling axis in Type 2 diabetes-associated cognitive decline: from mitochondrial DNA sensing to neurodegeneration.

Nitish Nirala, Omkar Kumar Kuwar, Dhrubalochan Rana, Dibya Sundar Padhy, Ram Kumar Choudhary.

  Type 2 diabetes mellitus (T2DM) is increasingly recognized as a major contributor to cognitive decline, substantially elevating the risk of dementia through mechanisms that extend beyond chronic hyperglycemia. Among the interconnected pathological processes underlying diabetic neurodegeneration, mitochondrial dysfunction has emerged as a pivotal upstream event that promotes oxidative stress, impairs mitophagy, and leads to the cytosolic release of mitochondrial DNA (mtDNA). Recent evidence identifies the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway as a critical innate immune sensor that detects aberrant cytosolic mtDNA and orchestrates sustained neuroinflammatory responses. Activation of the cGAS-STING axis initiates TBK1/IRF3- and NF-κB-dependent signaling, driving the production of type I interferons and pro-inflammatory cytokines that amplify glial activation, compromise blood-brain barrier (BBB) integrity, disrupt synaptic homeostasis, and suppress adult hippocampal neurogenesis, ultimately contributing to progressive cognitive impairment. Although the cGAS-STING pathway has been extensively investigated in infection, cancer, and autoimmune disorders, its mechanistic contribution to diabetes-associated cognitive decline remains insufficiently synthesized. This review proposes cGAS-STING as a central molecular hub that integrates mitochondrial damage with innate immune activation, thereby linking metabolic dysfunction to neurodegeneration. We critically evaluate current experimental and emerging clinical evidence and examine the interplay among cGAS-STING, mitochondrial quality control, neurovascular dysfunction, and key signaling networks, including AMPK/SIRT1/PGC-1α, the NLRP3 inflammasome, PI3K/Akt-mTOR, and autophagy. Finally, we discuss the therapeutic potential of targeting the cGAS-STING axis and identify major knowledge gaps that must be addressed to facilitate biomarker development and the development of disease-modifying interventions for T2DM-associated cognitive decline.

Keywords:  Diabetes mellitus; Mitochondrial dysfunction; Neurogenesis; Synaptic dysfunction; cGAS-STING signaling

DOI:  https://doi.org/10.1007/s00592-026-02802-5
Tissue Cell. 2026 Oct 11. pii: S0040-8166(26)00740-8. [Epub ahead of print]104(Pt 3): 104044

Mitochondrial-derived peptides in female reproduction: Emerging regulators of oocyte competence and novel therapeutic opportunities for infertility.

Zahra Rostami, Mina Galeshi, Abbas Mosapour.

  Female infertility affects approximately 17.5% of adults worldwide. Mitochondria are central to oocyte developmental competence, and a novel class of mitochondrial genome-encoded peptides, mitochondrial-derived peptides(MDPs) comprising MOTS-c, Humanin and small Humanin-like peptide2(SHLP2), regulates cellular metabolism, oxidative stress and apoptosis. This hypothesis-driven perspective aims to:(i) synthesize indirect evidence to construct a mechanistic framework for MDP involvement in oocyte physiology and female infertility;(ii) propose prioritized research questions; and(iii) delineate translational paths toward MDP-based biomarkers and therapeutics in assisted reproductive technology(ART). PubMed, Scopus and Web of Science were searched up to May 2025 using terms related to MDPs, oocytes, follicular fluid, ovarian aging and IVF. Bibliographies were hand-searched. The search yielded 312 records, of which 87 were retained. The three principal MDPs decline with age in humans, mirroring the age-related deterioration of oocyte quality. The reduced MOTS-c in polyendocrine metabolic ovarian syndrome (PMOS; formerly polycystic ovary syndrome, PCOS) (a 56% reduction in serum concentration versus controls, P < 0.001), provides preliminary evidence, albeit unreplicated and without ovarian sampling. Mechanistically, MDPs activate AMPK(MOTS-c), sequester pro-apoptotic Bax(Humanin), and reduce mitochondrial ROS while enhancing electron transport chain activity(SHLP2). Humanin is already known to be present in human follicular fluid and to associate with ovarian reserve and PMOS-related insulin resistance; we propose that this extends to MOTS-c and SHLP2, that composite MDP levels correlate with oocyte-specific quality parameters, and that a composite biomarker panel could improve IVF outcome prediction beyond AMH alone. MDPs(MOTS-c,Humanin,SHLP2) decline with age, regulate AMPK, suppress oxidative stress and inhibit apoptosis; processes that drive oocyte quality decline. Reduced MOTS-c in PMOS provides an initial, unreplicated clinical link. Convergent biology positions MDPs as promising candidates to improve IVF outcomes. Direct empirical testing, starting with quantification of MDPs in human follicular fluid and granulosa cells, is now warranted.

Keywords:  AMPK; Female infertility; Humanin; MOTS-c; Mitochondrial-derived peptides; Oxidative stress; SHLP2

DOI:  https://doi.org/10.1016/j.tice.2026.104044
Mol Nutr Food Res. 2026 Oct;70(19): e70619

Ergothioneine Mediated Neuroprotective Effects in the Nervous System.

Tanusree Saha, Robert D Frisina, Xiaoxia Zhu, Collin Park, Bo Ding, Joseph P Walton, Parveen Bazard.

  Ergothioneine (EGT), a micromolecular derivative of histidine containing sulfur, is found in various organisms, including humans. It demonstrates antioxidant properties, reduces inflammation, and potentially possesses antiaging effects for neurodegenerative conditions, positioning EGT as a potential candidate for health enhancement and healthy aging. EGT appears to offer strong protective properties at the cellular level and shows decreased concentration levels in blood plasma in different neurological conditions such as cognitive impairment, Parkinson's disease, macular degeneration, and other neurodegenerative diseases. Further, emerging evidence from both preclinical and currently limited clinical studies indicates EGT's therapeutic potential for neurological disorders. For instance, EGT treatment slowed the progression of age-related hearing loss and alleviated the cisplatin-induced hearing loss in mouse models, especially in male mice. Similarly, EGT intervention in older adults (aged 60 years or older) has shown some effectiveness in improving cognitive ability, memory, and sleep quality. In this review, we present a thorough examination of its function in neuroprotection, particularly within the nervous system and explore its potential intracellular targeting pathways and their underlying mechanisms.

Keywords:  antioxidant; brain; cognitive functions; ergothioneine; neuroprotection; nutraceutical

DOI:  https://doi.org/10.1002/mnfr.70619
J Exp Zool A Ecol Integr Physiol. 2026 Oct 15. e70140

Sex-Specific Early Life Corticosterone Stress-Coping Capacity Is Linked to Mitochondrial Content and Telomere Maintenance.

Mauricio Guillen-Parra, Alberto Velando, Bibiana Montoya, Roxana Torres.

  Glucocorticoids are upregulated during acute challenges, contributing to maintenance of energy balance. However, if this upregulation exceeds a threshold or becomes chronic, it can lead to harmful effects. Investigating the factors behind between-individual variation in the magnitude of the response to acute stress and how effectively individuals regulate this response to return to baseline glucocorticoid levels (recovery capacity), is therefore important. Glucocorticoid regulation may be influenced by mitochondrial content, as these hormones are produced in the mitochondria of the adrenal glands. Furthermore, early-life adversity can impair glucocorticoid regulation, and these effects may be mirrored by other mechanisms, such as telomere maintenance, suggesting possible correlations among these traits. In this study, we evaluated whether variation in corticosterone response to an acute challenge and recovery capacity in 27 Cocos Booby (Sula brewsteri) nestlings was related to mitochondrial DNA copy number (mtDNAcn), mass growth rate, and telomere dynamics during the first 30 days of life. We found sex differences in recovery capacity: females sustained higher corticosterone levels than males after an acute challenge. Higher mtDNAcn was associated with greater corticosterone increases and weaker recovery, suggesting that mtDNAcn reflects an individual's capacity to produce glucocorticoids. Finally, telomere dynamics, but not mass growth rate, were related to recovery capacity, a relationship only significant in females. Females with better telomere maintenance had weaker recovery capacity than those with poorer telomere maintenance. These results highlight links among glucocorticoid regulation, mtDNAcn, and telomere dynamics, suggesting that these traits are jointly shaped, likely through sex-specific pathways during early life.

Keywords:  corticosterone stress response; early development; mitochondrial content; sex differences; stress recovery capacity; telomere dynamics

DOI:  https://doi.org/10.1002/jez.70140
Cell Rep. 2026 Oct 10. pii: S2211-1247(26)01197-6. [Epub ahead of print]45(10): 118118

Dopamine-induced mitochondrial dysfunction activates cGAS-sTING to drive IL-6 secretion in macrophages.

Marzieh Daniali, Breana Channer, Erin O Curley, Amirali Amirfallah, Taylor Kist, John Montilla Luna, Stephanie Kosashvili, Lexi Sheldon, Kelly Stauch, Joshua G Jackson, Anneliese M Faustino, Thomas Beer, Hsin-Yao Tang, Stephanie M Matt, Will Dampier, Howard Fox, Peter J Gaskill.

  Despite growing evidence that dopamine acts as an innate immune inflammatory mediator, the molecular mechanisms by which dopamine modulates human immune function are incompletely defined. Here, we define the pathway in which dopamine induces robust IL-6 secretion in primary human monocyte-derived macrophages (hMDMs) through mitochondrial stress. Dopamine initiates a transient mitochondrial membrane depolarization that leads to sustained alterations in mitochondrial dynamics, including morphology and metabolism. These events promote the release of mtDNA into the cytoplasm, triggering the cGAS-STING pathway and NF-κB signaling. Pharmacological inhibition at multiple nodes of this pathway attenuates IL-6 secretion, establishing mitochondrial dysfunction and cGAS-STING signaling as central mediators of dopamine-driven IL-6 secretion. Variability in dopamine receptor expression across donors correlates with the magnitude of IL-6 responses. These findings highlight a potential link between dopamine signaling and systemic inflammation and suggest that differences in dopamine receptor expression may contribute to inter-individual variation in innate immune responses.

Keywords:  CP: immunology; IL-6; cGAS-STING; dopamine; immunopharmacology; immunoregulation; inflammation; macrophages; mitochondria; mitochondrial DNA; mtDNA

DOI:  https://doi.org/10.1016/j.celrep.2026.118118
J Alzheimers Dis Rep. 2026 Jan-Dec;10:10 25424823261449500

Spermidine protects mitochondria against amyloid-β oligomers.

Drake Mosca, Ekaterina Parfenova, Yuan Bie, Anthony Mutsaers, Paul A Spagnuolo.

   Background: Alzheimer's disease (AD) is a neurodegenerative condition characterized by amyloid-β (Aβ) plaques in the brain. In early pathological conditions, Aβ oligomers localize in mitochondria to promote disease progression by causing mitochondrial dysfunction.
Objective: Establish a robust AD pathological in vitro model and assess the therapeutic effect of spermidine (SPD) against extracellular Aβ oligomers.
Methods: In this study, high-resolution respirometry, flow cytometry, and immunoblotting techniques were used to characterize the negative effects of Aβ oligomer localization in mitochondria and assess the potential neuroprotective effects of SPD.
Results: Oligomeric Aβ accumulates in and causes mitochondrial dysfunction, as evidenced by increased mitochondrial superoxide production, decreased mitochondrial mass, and decreased maximal mitochondrial respiration and spare reserve capacity. SPD, an endogenously produced polyamine that can also be provided through exogenous supplementation, improved these markers and protected mitochondria of oligomer-treated cells.
Conclusions: SPD ameliorated mitochondrial dysfunction caused by Aβ oligomers in vitro.

Keywords:  Alzheimer's disease; Aβ oligomers; mitochondria; spermidine

DOI:  https://doi.org/10.1177/25424823261449500
Aging Dis. 2026 Oct 09.

GDF15 Induces Weight Loss with Diet- and Age-Dependent Metabolic Effects Across Tissues in Mice.

Laura Salmón-Gómez, Victoria Catalán, Beatriz Ramírez, Maite Aguas-Ayesa, Amaia Rodríguez, Sara Becerril, Gema Frühbeck, Javier Gómez-Ambrosi.

Growth differentiation factor 15 (GDF15) is a regulator of body weight and systemic homeostasis. However, the mechanisms underlying its effects remain unclear. This study aimed to determine whether diet, age, and sex influence GDF15's metabolic effects. Male and female mice aged 8 or 64 weeks were fed a normal diet (ND) or high-fat diet (HFD) for 20 weeks and were treated subcutaneously with recombinant GDF15 or vehicle for 3 weeks. Body weight and food intake were monitored. Epididymal white adipose tissue (eWAT), subcutaneous WAT (scWAT), brown adipose tissue (BAT), liver, and gastrocnemius muscle were analyzed by histology and gene expression. GDF15 reduced body weight, with greater effects in HFD-fed and aged mice. Reduced food intake was mainly observed in young HFD-fed mice. GDF15 improved glycemic control and exerted tissue-, diet-, and age-dependent effects. The liver showed greater transcriptional changes, especially in aged mice, although GDF15 also induced tissue-specific changes in BAT, gastrocnemius muscle, and eWAT. Gdf15 expression was more strongly induced by HFD in BAT and by aging in eWAT. These findings reveal that GDF15 exerts robust metabolic effects on body weight and glucose homeostasis, with age-dependent effects on food intake. GDF15 induced tissue-specific responses influenced by diet and age that may contribute to its systemic effects. These findings suggest that additional mechanisms beyond reduced food intake may contribute to the greater weight loss observed in aged mice. Together, our findings highlight age as a key determinant of the systemic response to GDF15.

DOI: https://doi.org/10.14336/AD.2026.0702
Appetite. 2026 Oct 12. pii: S0195-6663(26)00362-4. [Epub ahead of print] 108800

Comparative lifespan trajectories of brain energy metabolism in human and macaque.

Moohebat Pourmajidian, Bratislav Misic, Alain Dagher.

  The brain's high energy demands are met by a suite of metabolic pathways that selectively appropriate glucose across development, yet how this metabolic strategy changes across the lifespan and whether it is conserved across species remains incompletely understood. We previously mapped five core energy metabolism pathways across the human cortex and lifespan, revealing a fundamental dichotomy between anabolic and energy-producing pathway expression: the pentose phosphate pathway, which contributes to biomass, peaks prenatally, while glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation rise postnatally. Here, we extend the analysis to the rhesus macaque and show that the prenatal-to-postnatal transition is similar across the two species. Using the MitoCarta3.0 annotation framework, we further identify two consistent mitochondria-specific programs: a progressive decline in mitochondrial genome maintenance pathways, and a postnatal rise in the expression of genes involved in mitochondrial energy production and substrate utilization, replicated across human and macaque. Extending to mouse, rat, and chicken, we find this shifting transcriptome-level metabolic strategy is a conserved feature of vertebrate brain development. Finally, we map the cortical expression of mitochondria-localized pathway genes in the adult human cortex, finding that the anabolic-oxidative dichotomy follows in the mature brain. Together, these findings provide a comparative transcriptomic reference for studying brain energy metabolism across the lifespan.

Keywords:  Brain energy metabolism; Comparative energetics; Lifespan trajectory; Mitochondrial function; Neuroimaging transcriptomics

DOI:  https://doi.org/10.1016/j.appet.2026.108800
Pharmacol Ther. 2026 Oct 13. pii: S0163-7258(26)00157-9. [Epub ahead of print]288 109130

Mitochondrial dysfunction in Alzheimer's disease: mechanisms, pathogenic interplay, and therapeutic opportunities.

Baomin Dou, Jiming Chen, Huaning Zhao, Andrew Sun-Yan, Xiongwei Zhu, Ying Xu.

  Alzheimer's disease (AD) remains a major cause of dementia, yet effective disease-modifying therapies are still limited. Although amyloid-β (Aβ) and tau pathology remain core features of AD pathogenesis, they do not fully explain how these pathological alterations drive progressive cellular dysfunction. Increasing evidence suggests that mitochondria are involved at this critical interface. In AD, mitochondrial abnormalities impair energy production, compromise organelle quality control, disrupt calcium (Ca2+) homeostasis, and alter communication with the endoplasmic reticulum and glial cells. As these defects accumulate, neurons and glia become less able to maintain metabolic stability, redox balance, and synaptic function. Mitochondrial dysfunction is therefore relevant to AD not as a single isolated lesion, but as a convergent process through which metabolic failure, oxidative stress, mitochondrial DNA damage, inflammatory signaling, and defective cellular maintenance reinforce one another. This perspective also helps explain why disease progression is difficult to reverse once mitochondrial homeostasis has been broadly compromised. At the same time, this framework also points to therapeutic opportunities, as the mechanisms driving the development and progression of mitochondrial dysfunction may be amenable to intervention. However, many mitochondria-centered strategies remain preclinical or have yielded inconsistent clinical benefit. Current evidence supports mitochondrial dysfunction as both a useful mechanistic basis for understanding AD progression and a biologically meaningful, though challenging, therapeutic target.

Keywords:  Alzheimer’s disease; Bioenergetics; Dynamics; Mitochondria-associated membranes; Mitochondrial dysfunction; Mitophagy; Neuroinflammation

DOI:  https://doi.org/10.1016/j.pharmthera.2026.109130
Free Radic Biol Med. 2026 Oct 15. pii: S0891-5849(26)01214-1. [Epub ahead of print]

Redox resilience in skeletal muscle aging: cellular adaptations and exercise-mediated homeostasis.

Eva Tamayo-Torres, Miriam Martinez-Canton, Silvana Soto-Rodriguez, Abril Gorgori-Gonzalez, Julian Carretero, Juan Ignacio Cervera-Miguel, Olga Laosa, Leocadio Rodriguez-Mañas, Maria Carmen Gomez-Cabrera.

Aging progressively impairs skeletal muscle function, leading to sarcopenia, frailty, and loss of independence. Although oxidative stress has long been considered a central driver of muscle aging, increasing evidence indicates that reactive oxygen species (ROS) also serve essential signaling functions that coordinate mitochondrial remodeling, proteostasis, metabolism, and tissue repair. Consequently, age-related muscle dysfunction is increasingly understood as reflecting impaired adaptive redox signaling rather than excessive oxidant production alone. In this review, we propose the concept of redox resilience as an integrative framework describing the capacity of skeletal muscle to preserve structural integrity and functional performance through the dynamic regulation of oxidant production, antioxidant defenses, and redox-sensitive signaling in response to physiological challenges. We discuss how aging disrupts this resilience through impaired redox-sensitive signaling, including the attenuation of exercise-induced Nrf-2 activation, together with alterations in the multicellular organization of skeletal muscle. Recent advances in single-cell and single-nucleus transcriptomics have revealed that muscle aging involves profound remodeling of specialized myonuclear populations, stromal cells, immune cells, and intercellular communication networks, highlighting the multicellular complexity of skeletal muscle aging and providing a framework to investigate how redox-dependent processes may interact with tissue-wide signaling networks. We further examine how regular physical exercise reinforces redox resilience by promoting transient ROS-mediated signaling through NADPH oxidases, activation of Nrf-2 and PGC-1α-dependent pathways, mitochondrial quality control, and metabolic remodeling. These adaptations enhance the capacity of skeletal muscle to respond to physiological stress while preserving tissue homeostasis. Finally, we discuss future perspectives for targeting adaptive redox networks to promote healthy muscle aging and propose that restoring redox resilience may preserve physiological ROS signaling while strengthening endogenous antioxidant responses and limiting excessive oxidative damage, thereby contributing to the maintenance of muscle function and health span.

DOI: https://doi.org/10.1016/j.freeradbiomed.2026.10.023
Neurosci Biobehav Rev. 2026 Oct 13. pii: S0149-7634(26)00494-X. [Epub ahead of print] 107036

Mitochondrial Psychobiology.

Ana C Andreazza, Alexander Behnke, Juan P Bolanos, Jaime de Juan-Sanz, Elissa Epel, Michele K Evans, Lisa Feldman Barrett, Lauren E Gyllenhammer, Yusuke Hirabayashi, Michio Hirano, Fiona Hollis, D Parker Kelly, Christopher Kempes, Iris-Tatjana Kolassa, Nick Lane, Mary Kay Lobo, Lilianne R Mujica-Parodi, Aoife O'Donovan, Dost Ongur, Martin Picard, Sarah D Pressman, Carmen Sandi, Orian Shirihai, Caroline Trumpff, Lukas Van Oudenhove, Tor D Wager.

  A field that uses mitochondria to unify biological and psychological sciences and to better understand the basis of health has emerged-Mitochondrial Psychobiology. Mitochondria are the body's cellular hubs for energy transformation and signaling. Mitochondria regulate functions as diverse as metabolism, gene expression, and stress adaptation; consequently, their dysregulation is linked to most chronic illnesses and aging. Here, we propose that mitochondria provide a mechanistic bridge between body and the measurable functions of the mind, including perception, cognition, emotion, and behavior. From this perspective, mitochondria provide a scientifically tractable interface through which bioenergetic processes relate to subjective experiences and behaviors. We outline foundational principles for Mitochondrial Psychobiology, discuss the key gaps that the field needs to address to advance our understanding of mind-mitochondria relationships across the lifecourse, and review emerging approaches to probe the mind-mitochondria connection across levels. This stimulating scientific challenge is a unique opportunity to train the next generation of interdisciplinary scientists, resolve conceptual and technical challenges spanning temporal and spatial scales, and develop a more accurate, holistic model of health. Rooted in general energetic principles, mitochondrial psychobiology is poised to productively steer biomedicine over the coming decades.

Keywords:  bioenergetics; brain; environment; evolution; mitochondria; modeling; psychopathology; regulation; resilience; robustness; stress; transdisciplinary

DOI:  https://doi.org/10.1016/j.neubiorev.2026.107036
iScience. 2026 Oct 16. 29(10): 117646

Topical application of urolithin A activates mitophagy and enhances mitochondrial function to promote skin longevity.

Davide D'Amico, Julie Faitg, Frédéric Amaral, Carine Ballihaut, Andréane M Fouassier, Charlotte Tissot, Isha Rana, Julien Laboureau, Natascha Hennighausen, Marianne Brandt, Nicholas Kron, Xavier Marat, Chantal Jouy, Annie F Black, Gayané Azadiguian, Delphine Guillon, Jean-Thierry Simonnet, Chris Rinsch, Anurag Singh.

  Urolithin A (UA, Mitopure), a postbiotic that promotes mitophagy and mitochondrial function following oral administration, was evaluated for its effects on skin health in human skin models and when applied topically to healthy subjects in randomized clinical studies. UA tested in 2D and 3D reconstructed human skin and ex vivo human skin explants showed enhanced mitochondrial respiration, activated mitophagy markers, reduced inflammatory mediators and senescence-associated markers, and increased proteins involved in extracellular matrix structure and epidermal differentiation. Safety was confirmed in a human repeat-insult patch test. In randomized, placebo-controlled clinical studies, UA reduced periorbital wrinkle depth after 8 weeks and attenuated UVB-induced erythema. Skin transcriptomics supported increased extracellular matrix and epidermal development programs together with decreased inflammatory and senescence-associated signaling. These findings indicate that topical UA engages cellular pathways associated with skin resilience to promote skin health and longevity.

Keywords:  Ki-67; collagen III; collagen VII; elastin; filaggrin; inflammation; mitochondria; mitophagy; skin aging; urolithin A

DOI:  https://doi.org/10.1016/j.isci.2026.117646
Neurobiol Aging. 2026 Oct 11. pii: S0197-4580(26)00166-1. [Epub ahead of print]169 172-179

Association of mitochondrial copy number and heteroplasmy with cognitive function in the ACCORD trial.

Michelle C Odden, Yongmei Li, Vasantha Jotwani, Meghana S Eswarappa, Rebecca Scherzer, Michael G Shlipak, Dan E Arking, Wen Shi, Joachim H Ix, Robyn Jones, Anima Sharma, Lea McGeever, Pierre-Yves Desprez, Gregory J Tranah.

  Mitochondrial dysfunction has been implicated in cognitive decline and dementia, but the relationship between mitochondrial DNA (mtDNA) heteroplasmy and copy number with cognitive function remains poorly understood. We aimed to study these associations among individuals with diabetes who face elevated risk for mitochondrial dysfunction and cognitive impairment. We analyzed data from 954 participants (mean age 62.8 years, 52.1% female) in the Action to Control Cardiovascular Risk in Diabetes Blood Pressure trial. Mitochondrial heteroplasmy burden was quantified using the modified mitochondrial local constraint score sum (mMSS) from whole mitochondrial genome sequencing. Mitochondrial copy number was measured using quantitative PCR. Cognitive function was assessed using the Digit Symbol Substitution Test for processing speed and the Mini-Mental State Examination for global cognition at baseline, 20 months, and 40 months. Our primary regression models adjusted for demographics, cardiovascular risk factors, and mitochondrial haplogroup. Participants with mMSS > 0.5 had significantly worse processing speed at baseline compared to those with mMSS= 0 (β=-4.94 points, 95% CI: -9.44, -0.43) after adjustment. Higher mitochondrial copy number was associated with better processing speed at baseline among men (β=1.67 per SD, 95% CI: 0.31, 3.03). Neither heteroplasmy nor copy number was significantly associated with global cognition or with longitudinal cognitive decline. Higher mitochondrial heteroplasmy burden and lower copy number (in men) were associated with worse processing speed but not global cognition or cognitive decline. Mitochondrial dysfunction may contribute to domain-specific cognitive impairment in diabetes, with potential sex differences. Further research is needed to elucidate mechanisms and evaluate mitochondrial measures in brain tissue.

Keywords:  Cognition; Diabetes; Mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.neurobiolaging.2026.10.001
Aging Cell. 2026 Oct;25(10): e70714

The Human Ovary Exhibits Dynamic Molecular Remodeling in the Decades Post-Menopause.

Mark A Watson, Bikem Soygur, Christina D King, Pooja R Devrukhkar, Simon Melov, Elisheva D Shanes, Mary Ellen G Pavone, Francesca E Duncan, Birgit Schilling.

  The human ovary is among the first organs to show age-related functional decline, resulting in menopause. Beyond this transition, the postmenopausal ovary is often regarded as quiescent and remains poorly characterized. We analyzed the proteomes of healthy, non-pathological ovaries using mass spectrometry (data-independent acquisition) from 28 postmenopausal women (50-75 years old), stratified into three age groups (50-59, 60-69, ≥ 70). We quantified 5812 protein groups and observed progressive age-associated shifts, with 117 proteins significantly altered in the ≥ 70 versus 50-59 age comparison. Multivariate analysis demonstrated clear separation between 50-59 and ≥ 70-year-old age cohorts, with protein signatures shifting from RNA/gene-regulatory functions in younger ovaries to metabolic, trafficking, and innate immune/complement pathways in older ovaries. Across differential abundance, multivariate modeling, and covariate-adjusted linear modeling, we identified a convergent set of age-associated proteins that were integrated into the 26-protein Buck Postmenopausal Ovary Molecular Signature (BuckPOMS), a consensus molecular signature capturing progressive extracellular matrix remodeling, inflammatory signaling, and loss of structural and keratin-associated proteins with age. Representative BuckPOMS proteins, including the secreted matrisome proteins WNT4 and Fibromodulin (FMOD), were validated by immunohistochemistry. Pathway enrichment further identified an increase in inflammatory and matrisome pathways, and increased abundance of damage-associated secretory factors decades following menopause. These data fundamentally shift the notion of the postmenopausal ovary as an inert organ and instead demonstrate active and continuous molecular remodeling that has potential relevance to tissue signaling and implications for women's health.

Keywords:  aging; extracellular matrix; inflammation; postmenopausal ovary; proteomics; reproductive aging; senescence

DOI:  https://doi.org/10.1111/acel.70714
J Clin Aesthet Dermatol. 2026 Aug;19(8): 34-40

A Randomized Clinical Trial: Daily Photoprotection With a Combined Sunscreen-Antioxidant Formulation Preserves Mitochondrial DNA Integrity in Human Facial Skin In Vivo.

Amber Khalil, Hiva Fassihi, Mark A Birch-Machin, Jonathan Brookes, Amy Bowman, Gewei Zhu, Megan Hughes, Florence McDermott, Emma Craythorne.

OBJECTIVE: To evaluate whether a daily antioxidant-enriched sunscreen preserves mitochondrial DNA (mtDNA) integrity vs vehicle, whether habitual sunscreen users gain additional protection from antioxidants, and whether mtDNA swabs can detect individual-level responses.
METHODS: Adults completed a randomized, double-blind, vehicle-controlled 12-week trial. Cheek swabs collected at baseline and Week 12 underwent blinded quantitative polymerase chain reaction assays. mtDNA damage was expressed as ΔCt, where higher values indicate greater damage and a negative change reflects improved integrity. The primary outcome was change in ΔCt.
RESULTS: Forty-one participants provided valid samples (antioxidant sunscreen: n=19; vehicle: n=18). Mean ΔCt change favored the antioxidant sunscreen (-0.48 vs 0.35; P=0.06; Mann-Whitney U, P=0.07). Responder rates were higher with antioxidant sunscreen (73.7% vs 38.9%; Fisher exact, P=0.05). Among habitual sunscreen users, mtDNA integrity improved with antioxidant enrichment (median ΔCt: -0.67; P=0.04) and worsened with vehicle (median ΔCt: 0.58; P=0.03). In this subgroup, responder rates were also higher with active treatment (75% vs 25%; P=0.03). mtDNA integrity demonstrated a clear individual-level sensitivity to change.
LIMITATIONS: This was a single-site pilot study and lacked a no sunscreen-only comparator arm.
CONCLUSION: Daily use of an antioxidant-enriched sunscreen produced consistent molecular evidence of reduced mtDNA damage, including statistically significant within-participant improvement among habitual sunscreen users.

Keywords: Mitochondrial DNA damage; antioxidant sunscreen; in vivo biomarker; oxidative stress; photoprotection; quantitative PCR; randomized controlled trial
J Clin Aesthet Dermatol. 2026 Sep;19(9): 67-72

The Effects of Topical and Oral Creatine on Skin Firmness and Resilience: A Review.

Nicole Werpachowski, Lyudmyla Susla, Milana Stein, Karan Lal.

BACKGROUND: Skin quality declines with intrinsic aging, environmental damage, and oxidative stress. Loss of skin firmness, a hallmark of aging, results from collagen degradation and fibroblast dysfunction, weakening the extracellular matrix (ECM). This leads to increased laxity and wrinkle formation, known as dermatoporosis. Creatine, a naturally occurring compound essential for cellular energy metabolism, has emerged as a potential agent for improving skin firmness.
OBJECTIVE: To examine the effects of topical and oral creatine supplementation on skin firmness, focusing on cellular mechanisms and clinical evidence.
METHODS: A literature search was conducted in March 2025 using PubMed, Google, and Google Scholar. Studies investigating creatine's effects on the integumentary system were reviewed and summarized.
RESULTS: While clinical studies on creatine's effects on skin firmness are limited, in vivo and in vitro research suggest that topical creatine enhances skin elasticity and firmness while providing photoprotective benefits. These effects appear to be achieved with minimal risk when used at recommended doses. Although no direct studies on oral creatine's impact on skin firmness were found, its systemic absorption and demonstrated benefits in other physiologic processes suggest a potential role in skin health.
LIMITATIONS: While preliminary findings suggest dermatologic benefits of creatine, research is limited by a lack of studies isolating creatine's effects, scarce in vivo data, and insufficient long-term safety assessments.
CONCLUSION: Emerging evidence suggests that both oral and topical creatine may enhance skin firmness by supporting collagen metabolism and fibroblast function. However, further research is needed to establish clinical efficacy.

Keywords: Creatine supplementation; aging; collagen; metabolism; oral creatine; safety; topical creatine
Trends Neurosci. 2026 Oct 14. pii: S0166-2236(26)00190-6. [Epub ahead of print]

Resilience and vulnerability in the midbrain dopamine system during aging.

Gary McMurtrie, Samuel J Mabry, Jill R Glausier, Emily M Rocha, Zachary Freyberg.

  The midbrain dopamine system is integral to movement, reward, and motivation, and its dysfunction underlies a range of brain disorders. Age is a primary risk factor for many of these disorders, yet systematic analysis of how the dopamine system changes during healthy aging remains relatively understudied. In this review, we first examine the impact of healthy aging on the dopamine system across sexes and species, including flies, mice, rats, and humans. We next consider the neuroadaptive mechanisms that sustain dopamine neuron function with age. Finally, we contrast the molecular mechanisms of age-related neurodegenerative diseases with those of healthy aging, exploring the possibility that loss of neuroadaptive reserve drives dopamine neurodegeneration. Elucidating these neuroadaptive mechanisms could offer a path toward preserving dopamine neuron function across the lifespan and potentially preventing age-related neurodegeneration.

Keywords:  Parkinson’s disease; lifespan; metabolism; neurodegeneration; oxidative stress; ribosome

DOI:  https://doi.org/10.1016/j.tins.2026.09.008
Brain Behav Immun. 2026 Oct 15. pii: S0889-1591(26)00823-8. [Epub ahead of print]139 107075

Childhood trauma in women with HIV is associated with increased mitochondrial respiration despite reduced mitochondrial DNA copy number.

Hannah Stadtler, Maryam Jamil, L Ashley Cowart, Leah H Rubin, Gretchen N Neigh.

  Early life stress (ELS) is highly prevalent among women with HIV (WWH) and contributes to risk for brain health disorders. Mitochondria represent key regulators of cellular stress processes and may represent a key mechanism linking ELS to biological vulnerability. While mitochondrial dysfunction has been associated with ELS in other populations, it remains unknown whether ELS is related to multidimensional mitochondrial health in WWH. Thus, we examined associations between ELS and mitochondrial health metrics in WWH. Sixty-one WWH completed the Childhood Trauma Questionnaire (CTQ) and provided blood samples. Plasma and peripheral blood mononuclear cells (PBMCs) were isolated and used to assess mitochondrial bioenergetic function (Seahorse Cell Mito Stress Test), mitochondrial DNA copy number (mtDNAcn, qPCR), mtDNA integrity (qPCR), cell free mitochondrial DNA (cf-mtDNA, qPCR), and static mitochondrial protein expression (western blots). Linear regression models were used to evaluate associations between CTQ scores and mitochondrial outcomes. Higher CTQ scores were associated with increased basal respiration (β = 0.824, p = 0.012, q = 0.028), maximal respiration (β = 3.716, p = 0.014, q = 0.028), and spare respiratory capacity (β = 2.844, p = 0.026, q = 0.031). Conversely, higher CTQ scores were associated with lower mtDNAcn (β = - 2.369, p = 0.009, q = 0.018). No associations were observed with mtDNA integrity, cf-mtDNA, or mitochondrial protein expression. These findings demonstrate a divergent mitochondrial phenotype in WWH exposed to ELS, characterized by increased respiratory activity despite reduced mtDNA copy number. Mitochondrial health is potentially an integral consideration for understanding the link between ELS and biological vulnerability.

Keywords:  Early life stress; HIV; Mitochondria; Trauma; Women

DOI:  https://doi.org/10.1016/j.bbi.2026.107075
J Alzheimers Dis Rep. 2026 Jan-Dec;10:10 25424823261470071

Association between Gompertz law-based biological age (GOLD BioAge) and incident mild cognitive impairment: Modifying role of social activeness.

Yating Xiao, Li Li.

   Background: Mild cognitive impairment (MCI) is an important transitional stage between normal cognitive aging and dementia. Biomarker-based biological age may better capture physiological aging processes than chronological age, yet its association with the risk of developing MCI remains insufficiently studied.
Objective: We aimed to examine the association between Gompertz Law-Based Biological Age (Light BioAge) and incident MCI in a middle-aged and older Chinese population, and to explore whether social activeness modifies this association.
Methods: We used data from the China Health and Retirement Longitudinal Study, a nationally representative cohort. Light BioAge was calculated from chronological age, serum creatinine, fasting glucose, and C-reactive protein. Incident MCI was defined using age- and education-standardized cognitive assessments. Cox regressions were used to analysis.
Results: Among 9410 participants free of MCI at baseline, 1047 developed MCI during follow-up. Light BioAge was negatively associated with risk of MCI (hazards ratio (HR) = 0.99, 95% CI: 0.98-0.99). Compared to high Light BioAge, those in the moderate and low groups showed significantly lower risks of MCI (HR = 0.78, 95% CI: 0.65-0.94 and HR = 0.79, 95% CI: 0.65-0.97, respectively). The association were consistent across sex and different levels of social activeness, with no significant interaction observed.
Conclusions: Lower biological age, as estimated by Light BioAge, is independently associated with a reduced risk of MCI in middle-aged and older adults. The use of biomarker-based aging indicators may help identify individuals at higher risk of cognitive decline for early preventive strategies.

Keywords:  Alzheimer's disease; biological age; longitudinal study; mild cognitive impairment

DOI:  https://doi.org/10.1177/25424823261470071
Front Pharmacol. 2026 ;17 1896655

Four-week supplementation with a blackcurrant formulation enhances cognitive performance, reduces mental fatigue and modulates peripheral monoamine metabolism in older adults: a randomized, double-blind, placebo-controlled, crossover study.

Dominic Lomiwes, Catrin S Günther, Alexander P Kanon, Kim Lo, Andrew Scholey, Nayer Ngametua, Tania M Trower, Edward G Walker, Dwayne A Jensen, Janine M Cooney.

   Introduction: Age-related cognitive decline is an increasing concern in older adults. While blackcurrants (Ribes nigrum) have shown promise in improving cognitive outcomes in younger adults, their efficacy in supporting cognitive function in older adults is largely unexplored.
Methods: In this randomized, placebo-controlled, double-blinded crossover study of healthy older adults (62 ± 1 years), 26 of the 30 participants enrolled completed the study per protocol. Participants consumed either a placebo or a flavonoid-rich blackcurrant formula (BCF, 7.8 mg anthocyanins/kg body weight freeze-dried blackcurrant, 200 mg L-theanine, and 100 mg pine bark extract) in a beverage format daily for 4 weeks, with interventions separated by a two-week washout period. For each intervention, cognitive and mood outcomes were assessed following a single dose (acute) and after 4 weeks' supplementation. Platelet MAO-B activity, circulating neurotransmitter concentrations, and anthocyanin, L-theanine and sarmentosin bioavailability were measured from venous blood samples drawn at baseline, 1 h, 2.4 h and 4 wk after intervention supplementation.
Results: A significant reduction in Rapid Visual Information Processing (RVIP) false alarms (p = 0.022) and a strong trend in reduced mental fatigue (p = 0.046, q = 0.067) were measured following 4 weeks of BCF supplementation. Reduction in biomarkers of MAO activity were measured following acute supplementation with BCF, but not placebo, with significant treatment × time interactions (q < 0.01) for platelet MAO-B activity, plasma 5-hydroxyindoleacetic acid and 3,5-dihydroxyphenylglycine concentrations. These changes corresponded with significant reductions (q < 0.05) in circulating neurotransmitter metabolites xanthurenic acid, 3-methoxy-4-hydroxyphenylglycol and vanillylmandelic acid.
Conclusion: Findings from this study indicate that 4 weeks of BCF supplementation sustained attention in healthy older adults, extending evidence for BCF-related cognitive benefits across both younger and older populations.
Clinical Trial Registration: https://anzctr.org.au/, identifier: ACTRN12621001590853.

Keywords:  blackcurrant; cognitive function; l-Theanine; monoamine oxidase; mood; neurotransmitters; older adults

DOI:  https://doi.org/10.3389/fphar.2026.1896655
PLoS One. 2026 ;21(10): e0360683

Interventions with mitochondrial-related effects in older adults with type 2 diabetes: Protocol for a systematic review with conditional network meta-analysis.

Hao Liu, Aochuan Sun, Yu Deng, Yihan Li, Jiayu Hu, Zhengtang Liu.

INTRODUCTION: Mitochondrial dysfunction is central to type 2 diabetes mellitus (T2DM) pathogenesis, driving insulin resistance and pancreatic β-cell dysfunction. Age-related mitochondrial impairment worsens this in older adults, yet evidence on mitochondrial interventions for this group is limited. This protocol outlines a systematic review and conditional network meta-analysis of randomized controlled trials evaluating mitochondrial interventions in adults aged 60+ with T2DM.
OBJECTIVE: The primary objective of this systematic review and conditional network meta-analysis (NMA) is to evaluate the comparative efficacy and safety of diverse mitochondrial-related interventions, including pharmacological agents, nutritional supplements, and lifestyle modifications, relative to placebo, standard care, or no intervention, on mitochondrial function biomarkers in adults aged 60 years or older with type 2 diabetes mellitus (T2DM). Interventions with mitochondrial effects are operationally defined as those whose primary mechanism is known to target mitochondrial pathways or those that are explicitly evaluated for their effects on direct markers of mitochondrial function in the trial. The secondary objectives are: (1) to assess the impact of these interventions on glycemic and metabolic control outcomes including glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), fasting insulin, homeostatic model assessment of insulin resistance (HOMA-IR), body weight, and body mass index (BMI); (2) to conduct a conditional NMA to compare and rank the relative efficacy of different intervention categories if the evidence network is sufficiently connected and clinically coherent; and (3) to explore potential sources of heterogeneity (e.g., intervention duration, baseline HbA1c levels) via prespecified subgroup and sensitivity analyses.
METHODS AND ANALYSIS: Prepared per PRISMA-P, the review will follow PRISMA 2020 and PRISMA-NMA if applicable. Registered with PROSPERO (ID: CRD420251145356), searches will cover PubMed, Embase, Cochrane CENTRAL, Web of Science, and Scopus from inception to April 2026. Focused on T2DM, mitochondrial function/dysfunction, and interventions, age eligibility will be assessed during full-text screening. Primary analysis includes trials with participants aged 60+ or extractable data for this group; sensitivity analyses will include those with mean/median age ≥ 60. Two reviewers will handle screening, data extraction, and bias assessment using RoB 2.Analysis will focus on trials reporting mitochondrial function outcomes, categorized by biological domain, tissue source, and assay method. Glycemic control, geriatric health, and safety are secondary outcomes. Network meta-analysis will be conducted if a connected evidence network exists; otherwise, pairwise meta-analysis or narrative synthesis will be used. Random-effects models will be employed, with heterogeneity assessed via subgroup analysis and meta-regression. If significant heterogeneity persists, a Synthesis Without Meta-Analysis (SWiM) framework narrative review will be done. Evidence certainty will be appraised using GRADE and CINeMA.
ETHICS AND DISSEMINATION: Ethics approval is not required for this systematic review as the systematic review will include only previously anonymised data from primary studies. Dissemination of the findings of the final systematic review will occur through publishing in a peer-reviewed journal. PROSPERO registration number CRD420251145356.

DOI: https://doi.org/10.1371/journal.pone.0360683
Front Sci. 2026 ;4 1821393

Aging rate indicators and the search for anti-aging drugs.

Steven N Austad, Matt Kaeberlein, Richard A Miller.

  Evidence that drugs, diets, and single-gene mutations can slow aging and extend the healthy lifespan of mammals has begun to convert biogerontology from an observational science into one based on interventions that could provide people with additional years of healthy, productive life. However, the research and development of anti-aging drugs is hampered by the lack of instantaneous and continuous measures of the rate of aging itself. This article presents recent work on anti-aging drugs that are effective in mice, provides evidence for candidate "aging rate indicators" (ARIs), and outlines a roadmap for translating these into clinical research to slow aging in humans. Thus far, 14 agents or combinations have significantly increased the lifespan of mice in studies conducted under the Interventions Testing Program (ITP) of the National Institute on Aging, often when initiated in late adulthood. Recent evidence suggests that many, perhaps all, interventions that slow aging in mice induce common, shared changes in physiological status and molecular pathways. We have proposed 12 such mechanisms as candidate ARIs, i.e., measurable outcomes that reflect a slow-aging state and that could discriminate between normal mice (and perhaps humans) and those exposed to effective anti-aging interventions-thereby accelerating research. Research priorities now include testing the robustness of these ARIs, extending them to include plasma constituents, elucidating the mechanisms through which diverse interventions alter them, uncovering the links between the ARIs and late-life diseases, and extending research to dogs, non-human primates, and humans. The growing recognition of the legitimacy and promise of evidence-based interventions resulting from aging biology should elevate this field to a level of urgency and respect comparable to that of current research on individual age-related conditions.

Keywords:  aging; aging rate indicator; anti-aging; drug screening; lifespan; longevity; machine learning; rapamycin

DOI:  https://doi.org/10.3389/fsci.2026.1821393
Mitochondrion. 2026 Oct 15. pii: S1567-7249(26)00116-9. [Epub ahead of print] 102226

Mitofusin-2 (MFN2) is a critical regulator of metabolic homeostasis in neuronal cells: A metabolomic and proteomic study.

Prakash G Kulkarni, Soumya S Sahoo, Vaibhavi M Mohire, Shilpy Sharma, Jeetender Chugh, Tanushree Banerjee, Amul J Sakharkar.

  The role of mitofusin 2 (Mfn2) in mitochondrial metabolism and neurodegeneration is largely unknown. The current study probes the role of Mfn2 in mitochondrial biogenesis and metabolism in SH-SY5Y neuronal cells using multi-omics strategies. Mfn2 knockdown (KD) by siRNA treatment resulted into diverse proteomic and metabolomic changes. Furthermore, a battery of cellular and molecular analyses associated Mfn2-KD with increased oxidative stress, perturbed mitochondrial membrane potential and reduced mtDNA copy numbers in the neuronal cells. In addition, Mfn2-KD induced dramatic alterations in cell cycle profiles inclusive of proliferation and apoptosis. SWATH-MS-based analysis showed downregulation and upregulation of 11 and 22 differentially expressed proteins (DEPs), respectively, that serve in ribosomal biogenesis, translation, apoptosis, aging, TCA, and OXPHOS metabolic pathways. Among these proteins, TARBP emerged as a hub protein. 1H NMR-based metabolomic analysis showed alterations in 7 metabolites in the Mfn2-KD cells, which were associated with mitochondrial metabolism. Among these metabolites, taurine, a neuromodulator, was significantly downregulated after Mfn2-KD. Interestingly, supplementation of taurine restored the Mfn2-KD-induced deleterious alterations in mitochondrial physiology and cellular metabolomics in the neuronal cells. These results suggest the vital role of Mfn2 in mitochondrial functions in neuronal cells, and taurine emerges as a potential metabolite in Mfn2-linked mitochondrial dysfunction.

Keywords:  Metabolomics; Mitochondria; Mitochondrial dysfunction; Mitochondrial metabolism; Mitofusin; Neuronal cells; Proteomics

DOI:  https://doi.org/10.1016/j.mito.2026.102226
Mol Cell Endocrinol. 2026 Oct 14. pii: S0303-7207(26)00210-8. [Epub ahead of print] 112933

Astaxanthin-rich extract supplementation counteracts cardiac oxidative stress in a rodent model of diet-induced Metabolic Syndrome.

María Del Rosario Ferreira, Dante Selenscig, Matias Rodrigo Vargas, Paola Ingaramo, Pablo Collins, María Eugenia D'Alessandro.

  Growing evidence suggests that oxidative stress contributes to the pathophysiology of several disorders, making antioxidant-based interventions an active research area. Astaxanthin (ASTX) is a powerful antioxidant attracting research interest. Notably, the biological effects of ASTX depend on its natural source. We recently shown that an ASTX-rich extract derived from the freshwater crab Dilocarcinus pagei mitigates metabolic disturbances in major tissues involved in energy homeostasis (adipose tissue, liver, and skeletal muscle). Whether similar beneficial effects occur in cardiac tissue remains unknown. The aim of this work was to evaluate the effect of an ASTX rich-extract derived from D. pagei on cardiac redox disturbances developed in rats fed a high-sucrose diet (HSD), a model of Metabolic Syndrome (MetS). Male Wistar rats were fed for 90 days with a reference diet, a HSD, or a HSD plus a daily oral dose of an ASTX-rich extract (HSD+ASTX) (10 mg/kg body weight). Results showed that ASTX-rich extract prevented the HSD-induced increase in cardiac reactive oxygen species levels, alleviated oxidative stress, improved antioxidant capacity and was associated with changes in the protein expression of Nrf2 and phosphorylated NF-κB p65. Besides, HSD+ASTX-fed animals had lower blood pressure than HSD-fed rats at 30, 60 and 90 days of the experimental period. Serum CK-MB, AST, glucose and lipid levels were lower than those found in HSD-fed animals. The study provides novel insights into the beneficial effects of an ASTX-rich extract derived from D. pagei on cardiac redox imbalance and associated alterations induced by a HSD in male rats.

Keywords:  Astaxanthin; Heart; High-sucrose diet; Metabolic Syndrome; Oxidative status

DOI:  https://doi.org/10.1016/j.mce.2026.112933
Reproduction. 2026 Oct 12. pii: xaag128. [Epub ahead of print]

Nicotinamide mononucleotide supports the development of bovine embryo through enhancement of mitochondrial function in morula.

Shuting Ye, Shu Hashimoto, Masaya Yamanaka, Sanath Udayanga Kankanam Gamage, Yuki Inoue, Hisataka Iwata, Yoshiharu Morimoto, Daisuke Tachibana.

  NAD+ is an important regulator of cellular physiological processes. However, in the culture environment, NAD+ levels are predicted to decrease below physiological requirements. Therefore, we examined the effects of the NAD+ precursor nicotinamide mononucleotide (NMN) on NAD+ levels and viability of mammalian fertilized ova. NAD+ levels decreased during in vitro culture, but this decrease was alleviated by NMN. NMN also increased the blastocyst formation rate and accelerated the developmental rate. Transcriptome analysis showed that NMN induced significant changes in the expression of genes involved in mitochondrial function in morula, and that NMN increased mitochondrial membrane potential, oxygen consumption rate and mitochondrial DNA copy number of morula while reducing reactive oxygen species levels. The addition of NMN to the embryo culture medium increased NAD+ levels in embryos, boosted mitochondrial function at the morula stage, and enhanced their ability to develop into blastocysts.

Keywords:  Cattle; in vitro embryo production; nicotinamide adenine dinucleotide; transcriptome analysis

DOI:  https://doi.org/10.1093/reprod/xaag128
J Int Soc Sports Nutr. 2026 Dec 31. 23(sup1): 2732743

Load and breath-hold: impact of 7-day creatine monohydrate loading on breath-hold exercise performance - a double-blind randomized controlled trial.

Natalija Kurmazovic, Tzortzis Nomikos, Manolis Adamakis, Scott C Forbes, Giannis Arnaoutis, Brizita Djordjevic, Vanja Todorovic, Periandros Kritsiligkos.

   BACKGROUND: Creatine supplementation enhances anaerobic energy availability and buffering capacity; however, its impact on muscle work under voluntary breath-hold (BH) remains unexplored. BH exercise increases reliance on anaerobic ATP production and creates a metabolic environment in which phosphocreatine-derived ATP may be particularly valuable. The aim of this study was to determine whether creatine monohydrate loading improves BH exercise performance in trained BH divers.
METHODS: A double-blind, randomized, placebo-controlled study assessed the effects of a 7-day creatine monohydrate loading protocol (20 g/day) on performance outcomes and fatigue markers during BH exercise performed on a bicycle ergometer in 20 trained BH divers (18 males, 2 females; mean age 41.6 ± 8.6 years). The trial was registered at ClinicalTrials.gov (Identifier: NCT07233707) on 16th November 2025 under the title Load and Hold: Impact of 7-Day Creatine Monohydrate Loading on Breath-Hold Cycling Performance (BREATHE-C). Testing consisted of a brief warm-up followed by a maximal cycling trial performed on a single breath, during which participants aimed to cover the greatest possible distance. Following pre-supplementation testing, participants were randomly assigned to either the creatine monohydrate (CR) or the placebo (PL) group. Pre- and post-supplementation measurements included total work (TW), time to exhaustion (TTE), peripheral blood lactate accumulation (LA), mean partial pressure of carbon dioxide (pCO₂) in exhaled air following BH exercise, and ratings of perceived exertions for BH (RPE-BH) and muscle fatigue (RPE-MF). In addition, participants underwent dual-energy X-ray absorptiometry to assess changes in body composition.
RESULTS: Significant Time × Group interactions were observed for TW (p = 0.011), TTE (p = 0.028), and fat-free mass (p = 0.017), with greater changes observed following creatine supplementation compared to PL. Furthermore, there was a significant Time × Group interaction for LA (p = 0.003), with greater changes observed in the PL group compared to CR. No significant between-group differences were observed for pCO₂, RPE-BH, RPE-MF, fat mass, or total body mass.
CONCLUSIONS: Creatine enhanced performance, as reflected by increases in TW and TTE, without elevating RPE-BH, although a slight increase in RPE-MF was observed. LA was lower in the CR compared to PL group, despite greater performance improvements. Overall, creatine appears to enhance BH exercise performance in trained BH divers, suggesting a potentially effective ergogenic strategy for BH-related sports.

Keywords:  Breath-hold; anaerobic endurance; creatine monohydrate; loading; performance

DOI:  https://doi.org/10.1080/15502783.2026.2732743
Front Neurosci. 2026 ;20 1879347

Influence of a full-spectrum aqueous extract of black cardamom (Amomum subulatum Roxb.) fruits on focus/alertness and executive function: a randomized, double-blind, placebo-and active- controlled, 14-day comparative study in healthy working professionals.

Jestin V Thomas, M E Mohan, Syam S Das, Nithyanandam Allimuthu, Sheena Devasia, P A Aneesa, Krishnakumar Illathu Madhavamenon, Baby Chakrapani Pulikkaparambil Sasidharan.

   Background: Nootropics enhance cognitive functions, including memory, attention, alertness, mood, and reaction time, through diverse neurobiological mechanisms. Caffeine, one of the most widely consumed nootropics, improves cognitive performance primarily by promoting wakefulness and alertness; however, these effects are generally transient. Consequently, there is growing interest in plant-derived, food-grade nootropics that can provide sustained cognitive benefits with a favorable safety profile. In this context, the nootropic efficacy of a full-spectrum aqueous extract of black cardamom fruits (MA2-24), administered alone and in combination with caffeine, was evaluated in the clinical trial.
Methods: This randomized, double-blind, placebo- and active-controlled, 4-arm parallel group study for 14 days included healthy participants randomized into four groups (n = 24/group): placebo (250 mg), MA2-24 (250 mg), caffeine (200 mg), or MA2-24 + caffeine (250 + 200 mg). Cognitive performance was assessed on the 1st, 7th and 14th day at 1-, 3-, 5-, and 8-h post-intervention time points using validated CNS Vital Signs (CNSVS) tasks.
Results: Linear mixed-effects analyses revealed significant effects of treatment, study day, and post-dose assessment time on cognitive performance, with significant interaction effects across outcomes. Supplementation with MA2-24 improved cognitive performance, particularly in measures of attention, processing speed, cognitive flexibility, and executive function, as reflected by increased correct responses, faster reaction times, and fewer errors in the Shifting Attention, Symbol Digit Coding, and Stroop tests. Significant improvements with MA2-24 were observed during the early post-dose period (1-3 h) across multiple cognitive outcomes compared with placebo (p < 0.05). Co-administration of MA2-24 with caffeine produced greater improvements at the later post-dose assessments (5-8 h), particularly on Day 14 (p < 0.05).
Conclusion: CNSVS tests demonstrated that MA2-24 possesses significant nootropic potential in domains of attention, cognitive flexibility, executive function and processing speed, as evidenced by increased correct responses, faster reaction times, and fewer errors when consumed both as a standalone intervention and in combination with caffeine.
Clinical trial registration: https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=MTE0NzIx&Enc=&userName=, identifier CTRI/2024/09/074472.

Keywords:  Amomum subulatum; CNS vital signs; black cardamom; caffeine; cognition; executive function

DOI:  https://doi.org/10.3389/fnins.2026.1879347
Ageing Res Rev. 2026 Oct 14. pii: S1568-1637(26)00412-5. [Epub ahead of print]123 103420

Turning back the ageing clock? Brain age in neuroprotective and clinical interventions.

Yuke Luo, James H Cole, Hanna Lu.

  Neuroimaging-derived brain age has emerged as an intuitive marker of brain health and cognitive longevity. The difference between brain age and chronological age, termed brain-predicted age difference (brain-PAD), quantifies deviation from normative brain ageing and may help evaluate whether interventions could attenuate brain ageing trajectories. This review synthesizes the methodological foundations of brain age estimation, factors linked to brain-PAD across healthy ageing and disease, evidence from clinical interventions, and emerging translational applications in clinical trials. Across non-clinical and clinical populations, older-appearing brains are associated with poorer cognitive and physical function, greater physiological burden, higher mortality risk, cardiometabolic vulnerability, and a range of neurological and psychiatric disorders. Evidence from interventions remains limited and heterogeneous. Exercise provides the clearest proof-of-concept that brain-PAD is potentially modifiable, whereas dietary interventions and multidomain lifestyle programmes have produced suggestive but preliminary evidence; cognitive, sleep, and mind-body interventions have yielded sparse or mixed findings. In clinical settings, brain-PAD shows promise for predicting disease conversion, disability progression, and treatment response, and may support trial stratification, enrichment and monitoring. Evidence that medication, neuromodulation, or other interventions reliably normalize brain-PAD, however, remains inconsistent. We argue that brain-PAD is a useful but biologically nonspecific, model-derived biomarker. Its interpretation critically depends on pipeline choice, harmonization, age-bias correction, and longitudinal validity. For now, brain-PAD is best regarded as a complementary biomarker and exploratory outcome rather than a validated surrogate endpoint. Future progress will require standardized methods, validation in representative populations and prespecified longitudinal cohorts that links brain-age changes to meaningful clinical outcomes.

Keywords:  Brain age; biological ageing; brain-predicted age difference; clinical trials; lifestyle intervention; neuroimaging biomarker; neuroprotection

DOI:  https://doi.org/10.1016/j.arr.2026.103420
Cell Rep. 2026 Oct 14. pii: S2211-1247(26)01240-4. [Epub ahead of print]45(10): 118161

Mitochondrial stress induces transcription of cytosolic and mitochondrial protein synthesis components via NHR-180.

Avijit Mallick, Theresa Ramalho, Levi Ali, Yunguang Du, Duy Hoang, Rui Li, Pooja Rai, Sookyung Kim, Rakeyah Ahsan, Ala M Shaqra, Andreas Bergmann, Celia A Schiffer, Lihua Julie Zhu, Brian Kelch, Kuang Shen, Cole M Haynes.

  The mitochondrial unfolded protein response (UPRmt), which promotes mitochondrial biogenesis and proteostasis, is regulated by the transcription factor ATFS-1. In C. elegans, impaired atfs-1 expression perturbs mitochondrial function and slows development. Here, using an RNAi suppressor screen, we find that inhibition of the nuclear hormone receptor NHR-180 increases mitochondrial function and developmental rate in atfs-1(null) worms. NHR-180 levels increase and become more nuclear-localized during mitochondrial dysfunction, inducing transcription of genes required for protein synthesis on cytosolic and mitochondrial ribosomes. The NHR-180 ligand-binding domain interacts with AMP, suggesting that NHR-180 may link cellular energy status to protein synthesis during mitochondrial stress. However, NHR-180-dependent activity is associated with exacerbated mitochondrial dysfunction. Consistent with these findings, inhibition of the S6 kinase homolog RSKS-1 increases mitochondrial function in atfs-1(null) worms. S6 kinase inhibition also increases respiration and mitochondrial DNA (mtDNA) content in mammalian ATF5-knockout cells and oxidative phosphorylation (OXPHOS)-deficient models.

Keywords:  ATFS-1; CP: molecular biology; NHR-180; OXPHOS; RSKS-1, S6K, ATF5; mitochondria; mtDNA; protein synthesis

DOI:  https://doi.org/10.1016/j.celrep.2026.118161