bims-mistre 2026-10-04 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–10–04
eleven papers selected by
Ellen Siobhan Mitchell, MitoQ

Therapeutic potential of MitoQ, a mitochondria-targeted antioxidant, in age-related physiological dysfunction.
Myokines and mitochondrial function in cardiometabolic diseases.
Mitochondrial-Targeted Phytochemicals in Reproductive Aging: Mechanisms and Translational Potential.
GDF15 as a sentinel of metabolic integrity: a narrative review of stress signaling, multisystem pathophysiology, and therapeutic potential.
Glutathione in brain oxidative stress: from redox chemistry to clinical imaging.
Mitochondrial membrane lipid cardiolipin controls fiber-type adaptations in aging muscle via estrogen-related receptor γ.
Mitochondrial Dysfunction in Type 2 Diabetes and Metabolic Syndrome: Mechanisms, Biomarkers, and Emerging Therapies.
Elamipretide Rejuvenates Oocyte Quality and Restores Female Fertility During Reproductive Aging.
Repurposing MitoQ10 as a Therapeutic for Established Alzheimer's Disease Pathology.
A Randomized, Double-Blind, Placebo-Controlled Trial Comparing the Effects of Commercially Available Ubiquinone, Ubiquinol, and Geranylgeraniol Dietary Supplements on Plasma CoQ10 Concentrations.
Neuroenergetic flexibility in the aging brain: Cellular mechanisms and diet-induced metabolic switching.

Geroscience. 2026 Sep 28.

Therapeutic potential of MitoQ, a mitochondria-targeted antioxidant, in age-related physiological dysfunction.

Siyun Kim, Sung Gi Noh, Minje Ji, Kai Chen, George A Kuchel, Iman M Al-Naggar, Oh Sung Kwon.

  Aging is an inevitable and progressive physiological process marked by a decline in cellular function, accumulation of somatic mutations, decreased ability to maintain homeostasis, and increased tissue and organ dysfunction. These changes contribute to the onset and progression of various age-related diseases. Accumulation of reactive oxygen species (ROS) has been identified as a key mediator of the aging process. Mitochondria, the primary producers of ROS, accumulate defects with aging, leading to increased mitochondrial oxidative stress. These defective mitochondria are both a source and a target of oxidative stress, creating a vicious cycle that accelerates aging and the progression of age-related diseases. Consequently, targeting mitochondria represents a promising therapeutic approach to prevent aging-related physiological dysfunction. MitoQ, a mitochondria-targeted antioxidant, has been extensively studied due to its ability to effectively scavenge mitochondria-derived ROS, owing to its lipophilic cation properties. This review explores the effects of MitoQ on aging-associated physiological dysfunction, specifically exploring its impact on cardiovascular, neuronal, and skeletal muscle functions. By addressing the central role of mitochondrial oxidative stress, we propose that MitoQ represents a promising strategy to counteract aging-associated physiological dysfunction.

Keywords:  Age-related disease; Aging; MitoQ; Mitochondria-derived ROS; Mitochondria-targeted antioxidants; Oxidative stress

DOI:  https://doi.org/10.1007/s11357-026-02515-1
J Physiol Biochem. 2026 Oct 02. pii: 99. [Epub ahead of print]82(1):

Myokines and mitochondrial function in cardiometabolic diseases.

Jairo E Saavedra, Jaime Gallo-Villegas, Juan C Calderón.

  Cardiometabolic diseases (CMD) encompass a group of disorders sharing a common pathophysiology that increases the risk of cardiovascular disease and mortality. Key events underlying CMD pathophysiology include insulin resistance, low-grade inflammation, altered hormonal and myokine profiles, and mitochondrial dysfunction. The latter manifests as reduced mitochondrial mass and oxidative function, increased oxidative stress, altered Ca2+ handling and decreased mitochondrial membrane potential. Skeletal muscle plays a pivotal role in CMD pathophysiology through two main mechanisms: i) the storage and oxidation of energy substrates and ii) the release of myokines, which in turn modulate metabolism and mitochondrial function. Here, we propose that the unfavorable myokine profile associated with CMD pathophysiology leads to mitochondrial alterations, and that restoring a healthy myokine profile helps improve mitochondrial structure, function, and overall metabolic health. To test this idea, in this narrative review, we critically present evidence of an altered myokine profile in CMD and highlight the most important mitochondrial alterations in CMD before examining the direct effect of specific myokines on mitochondria and CMD-associated mitochondrial dysfunction. Finally, we summarize the effects of therapeutic interventions on both the myokine profile and mitochondrial function, also appraising human trials that use myokine-based interventions to improve CMD. We focus on molecular mechanisms and causal relationships, while also indicating novel perspectives in the field. Understanding the role of mitochondria in the effect of myokines on metabolic health may open new preventive and therapeutic strategies for addressing CMD more efficiently.

Keywords:  Healthy lifestyle; Mitochondria; Myokines; Obesity; Skeletal muscle

DOI:  https://doi.org/10.1007/s13105-026-01233-8
Reprod Med Biol. 2026 Jan-Dec;25(1):25(1): e70086

Mitochondrial-Targeted Phytochemicals in Reproductive Aging: Mechanisms and Translational Potential.

Binarwan Halim, Hilma Putri Lubis, Rony Abdi Syahputra.

   Purpose: Reproductive aging is increasingly recognized as a major contributor to infertility in both women and men. Although traditionally linked to endocrine decline, emerging evidence suggests that mitochondrial dysfunction is a central mechanism underlying impaired gamete quality and reduced reproductive capacity. This review aimed to evaluate the role of mitochondrial deterioration in reproductive aging and to examine the therapeutic potential of mitochondrial-targeted phytochemicals.
Methods: A narrative review of experimental, translational, and clinical studies was conducted focusing on mitochondrial dynamics, oxidative stress, bioenergetic impairment, and phytochemical-based interventions in reproductive aging. Relevant evidence involving oocytes, spermatozoa, and the reproductive microenvironment was critically synthesized.
Results: Aging-associated mitochondrial dysfunction was consistently associated with impaired ATP production, excessive reactive oxygen species generation, mitochondrial DNA damage, and disrupted cellular homeostasis, leading to reduced oocyte competence, sperm motility, and embryonic development. Several phytochemicals, including resveratrol, quercetin, epigallocatechin gallate, astaxanthin, lycopene, berberine, and coenzyme Q10, demonstrated protective effects through modulation of SIRT1-PGC-1α, AMPK, Nrf2, and PINK1-Parkin signaling pathways.
Conclusions: Targeting mitochondrial bioenergetics with phytochemicals may provide a promising strategy for preserving fertility and extending reproductive lifespan, although further large-scale clinical validation is required.

Keywords:  fertility preservation; gamete bioenergetics; mitochondrial dysfunction; phytochemicals; reproductive aging

DOI:  https://doi.org/10.1002/rmb2.70086
Front Endocrinol (Lausanne). 2026 ;17 1885104

GDF15 as a sentinel of metabolic integrity: a narrative review of stress signaling, multisystem pathophysiology, and therapeutic potential.

Tao Nie, Hongmei Song, Xiaofang Shen, Liufeng Mao.

  Growth differentiation factor 15 (GDF15) is a stress responsive cytokine belonging to the transforming growth factor-β (TGF-β) superfamily, serving as a sentinel of metabolic integrity. Its expression is induced by multiple convergent stress pathways, including the integrated stress response (ISR), endoplasmic reticulum (ER) stress, oxidative stress, inflammation, and hypoxia. GDF15 is secreted by a wide range of organs, such as adipose tissue, skeletal muscle, liver, heart, kidney, immune cells, and the central nervous system, with the relative contribution of each tissue varying across different physiological and pathological states. Through the hindbrain GFRAL-RET axis, GDF15 suppresses appetite and regulates energy balance, while also exerting peripheral effects on mitochondrial function, insulin sensitivity, and inflammatory responses. Transient GDF15 elevation in response to acute stressors supports adaptive metabolic resilience and tissue protection. In contrast, chronic and sustained elevation signals progressive metabolic dysfunction, organ impairment, and poor prognosis in conditions including obesity, metabolic dysfunction associated steatotic liver disease (MASLD), diabetes, and cardiovascular disease. Importantly, the biological impact of GDF15 is modified by factors such as age and metabolic context, which may shift the balance between adaptive and maladaptive outcomes and account for much of the predictive signal in clinical studies. Although GDF15 holds promise as a prognostic biomarker and a therapeutic target, its clinical translation is hindered by two major challenges: its dual protective and pathological roles, and an incomplete understanding of non-GFRAL signaling pathways. This narrative review summarizes the regulatory networks, tissue sources, and context-dependent functions of GDF15, with an emphasis on its roles in cardiometabolic homeostasis and the potential for future precision therapeutic strategies. We present the sentinel model as a working hypothesis that generates testable predictions, rather than as a proven biological mechanism. The acute-adaptive versus chronic-maladaptive distinction, while conceptually useful, requires validation through measurable parameters including concentration thresholds, temporal dynamics, and tissue specific contributions.

Keywords:  GDF15; GFRAL; cardiometabolic disease; metabolic integrity; obesity

DOI:  https://doi.org/10.3389/fendo.2026.1885104
Arch Toxicol. 2026 Sep 30.

Glutathione in brain oxidative stress: from redox chemistry to clinical imaging.

Koji Aoyama.

  Glutathione (GSH), a tripeptide composed of glutamate, cysteine, and glycine, is the most abundant intracellular low-molecular-weight thiol and serves as a central regulator of cellular redox homeostasis. In addition to its well-established roles in antioxidant defense and detoxification, GSH is essential for maintaining mitochondrial function and cellular viability. Since its discovery more than a century ago, extensive research has progressively revealed the diverse biological functions of GSH. More recently, growing evidence from experimental and clinical studies has demonstrated that disruption of GSH homeostasis is a common feature of multiple neurodegenerative diseases. Because the central nervous system consumes large amounts of oxygen, contains abundant oxidizable lipids, and possesses limited regenerative capacity, maintenance of neuronal GSH homeostasis is indispensable for protecting the brain against oxidative injury. Recent advances have further demonstrated that neuronal GSH synthesis is tightly regulated through specialized mechanisms, including astrocyte-neuron metabolic coupling and excitatory amino acid carrier 1-dependent cysteine transport. This review summarizes the historical development of GSH research, current understanding of the molecular mechanisms regulating brain GSH homeostasis, and how these mechanisms are disrupted in major neurodegenerative diseases. Finally, we discuss promising therapeutic strategies aimed at restoring endogenous neuronal GSH homeostasis and highlight the potential of brain GSH as both a biomarker and therapeutic target for oxidative stress-related neurodegenerative diseases.

Keywords:  EAAC1; Glutathione; Magnetic resonance spectroscopy; Neurodegeneration; Oxidative stress

DOI:  https://doi.org/10.1007/s00204-026-04545-2
Nat Aging. 2026 Sep 29.

Mitochondrial membrane lipid cardiolipin controls fiber-type adaptations in aging muscle via estrogen-related receptor γ.

Fabian Finger, Mikkel Frost, Shinya Watanabe, Tao Ma, Taewook Kang, Dipsikha Biswas, Ruben Zapata-Perez, Vincent Anton, Lucile Dollet, Lasse K Markussen, Nanami Senoo, Iuliia Karavaeva, Astrid Linde Basse, Oksana Dmytriyeva, Tara TeSlaa, Jesper F Havelund, Amy M Ehrlich, Marta Moreno-Torres, Caio Yogi Yonamine, Nicoline R Andersen, Ida Blom, Francisco Garcia-Carrizo, Piyarat Siripoksup, Magnus Asping, Thomas S Nielsen, Marcus Nygård, Anders B Klein, Andrey Tvardovskiy, Trine S Nicolaisen, Carlos Durantez-Fernández, Klaus Qvortrup, Clara Prats, Joshua D Rabinowitz, Christoffer Clemmensen, Lykke Sylow, Juleen R Zierath, Jonas T Treebak, Tim J Schulz, Trisha J Grevengoed, Steven M Claypool, Julien Prudent, Rob C I Wüst, Susanne Mandrup, Riekelt H Houtkooper, Kei Sakamoto, Nils J Færgeman, Martin R Larsen, Katsuhiko Funai, Steen Larsen, Zachary Gerhart-Hines.

Aging paradoxically leads to both a decline in skeletal muscle mitochondrial function and a shift in muscle composition that favors fibers rich in mitochondria. Yet the biological rationale and mechanism underlying this phenomenon remain largely unknown. Here we show that synthesis of the mitochondrial membrane lipid, cardiolipin, causally links mitochondrial dysfunction to fiber-type adaptations in aging mouse and human skeletal muscle. By mimicking the aging decline of skeletal muscle cardiolipin levels in young mice using inducible tissue-specific cardiolipin synthase 1 (Crls1) deletion, we could reproduce key aging hallmarks, including the shift from glycolytic to oxidative fibers. This shift is mediated by mitochondria-to-nucleus signaling through the nuclear receptor, estrogen-related receptor γ, which promotes reactive oxygen species-sensitive glucose uptake and enhanced glycolytic rerouting to sustain antioxidant defenses. Restoring Crls1 expression in adult Crls1 knockout mice reestablishes cardiolipin levels, initiates reversal of muscle atrophy and fully rescues premature mortality. These findings reveal how changes in a mitochondrial membrane lipid cell autonomously orchestrate fiber-type adaptations in aging and myopathies.

DOI: https://doi.org/10.1038/s43587-026-01227-7
Diabetes Metab Syndr Obes. 2026 ;19 627029

Mitochondrial Dysfunction in Type 2 Diabetes and Metabolic Syndrome: Mechanisms, Biomarkers, and Emerging Therapies.

Hamzah M Alghzawi, Salma Younas, Sweta Sahu, Soha Farooq, Muhammad Nafees, Saleh Mohammed.

   Background: Mitochondrial dysfunction is increasingly recognized as a bidirectional component of type 2 diabetes (T2D) and metabolic syndrome, linking nutrient excess, lipotoxicity, oxidative stress, inflammation, impaired insulin signaling, and pancreatic β-cell failure. However, its causal position and clinical actionability remain uncertain because mitochondrial abnormalities vary by tissue, disease stage, and metabolic phenotype.
Objective: To critically synthesize mechanistic, biomarker, imaging, and therapeutic evidence concerning mitochondrial dysfunction in T2D and metabolic syndrome, with emphasis on evidence maturity and clinical translation.
Methods: We conducted a structured narrative review of preclinical, translational, and clinical literature published primarily from 2015 through 2025. The search intentionally included established glucose-lowering therapies and selected mitochondria-directed agents and was not intended to be exhaustive. Because this was not a systematic review, no PRISMA flow diagram, formal risk-of-bias assessment, or standardized evidence grading was performed.
Results: Mitochondrial abnormalities in T2D include impaired oxidative phosphorylation, excessive reactive oxygen species, altered fission-fusion and mitophagy, disrupted calcium handling, metabolic inflexibility, and β-cell bioenergetic failure. The evidence supports a bidirectional model in which inherited susceptibility, aging, nutrient overload, visceral adiposity, lipotoxicity, and inflammation can impair mitochondria, while mitochondrial stress further amplifies insulin resistance and organ dysfunction. Candidate biomarkers and imaging methods remain predominantly research tools because specificity, assay standardization, validated thresholds, and prospective clinical utility are limited. Exercise, weight reduction, GLP-1 receptor agonists, and SGLT2 inhibitors have established clinical benefits and may improve mitochondrial biology indirectly or directly; in contrast, NAD+ precursors, targeted antioxidants, mitophagy enhancers, and other dedicated mitochondrial modulators remain investigational, with target engagement generally exceeding demonstrated glycemic benefit.
Conclusion: Mitochondrial dysfunction is best understood as a context-dependent driver, consequence, and amplifier of metabolic disease rather than a universal single cause. Translation will require standardized biomarker panels, noninvasive phenotyping, adequately powered randomized trials with longer follow-up, and prospective identification of patients whose mitochondrial phenotype is likely to be treatment-responsive.

Keywords:  emerging therapies; lipotoxicity; metabolic syndrome; mitochondrial biomarkers; mitochondrial dysfunction; oxidative phosphorylation; type 2 diabetes

DOI:  https://doi.org/10.2147/DMSO.S627029
Aging Cell. 2026 Oct;25(10): e70749

Elamipretide Rejuvenates Oocyte Quality and Restores Female Fertility During Reproductive Aging.

Hao-Lin Zhang, Yue Wang, Caizhu Wang, Xin Guo, Huanhua Chen, Yu-Xuan Hou, Xuan Wu, Zi-Jian Wu, Wen-Lin Pan, Rui-Jie Ma, Ping-Shuang Lu, Jinhui Shu, Shao-Chen Sun.

  Aging represents a major contributor to the deterioration of female fertility, with oocyte quality being the central determinant of ovarian aging, a key factor underlying infertility. Although several natural compounds with anti-aging activity have been documented, highly effective strategies to reverse ovarian aging remain elusive. Here, we report that the peptide elamipretide preserves ovarian function and sustains female fertility during maternal aging. We found that elamipretide administration increases litter size in aged mice and ameliorates oocyte quality decline. Metabolomic and transcriptomic profiling revealed substantial restoration of multiple biological processes in aged oocytes after elamipretide injection. Elamipretide improved both nuclear and cytoplasmic maturation of aged oocytes, accompanied by enhanced cytoskeletal dynamics, mitochondrial metabolism, and organelle reorganization. Mechanistically, elamipretide alleviated age-associated oocyte maturation defects through synergistic activation of the vitamin B6-VEGF axis. Furthermore, elamipretide significantly promoted maturation, fertilization, and cleavage of aged human oocytes. Elamipretide treatment also rescued the developmental competence of porcine oocytes under oxidative damage. Collectively, this study identifies a novel peptide therapeutic candidate for aging-related infertility, showing that elamipretide restores the quality of aged oocytes for fertility by coordinately boosting nuclear and cytoplasmic maturation via activation of the VEGF signaling pathway.

Keywords:  aging; fertility; oocyte; peptide; reproduction

DOI:  https://doi.org/10.1111/acel.70749
Aging Dis. 2026 Sep 22.

Repurposing MitoQ10 as a Therapeutic for Established Alzheimer's Disease Pathology.

Mohit Kumar, Sudipta Ray, Susmita Sil.

Alzheimer's Disease (AD) is characterized by progressive amyloid accumulation, neuroinflammation, and neuronal loss, yet therapies targeting amyloid alone provide limited clinical benefit. Here, we evaluated whether pharmacological targeting of mitochondrial redox dysfunction using MitoQ10 (MitoQ), a mitochondria-targeted antioxidant, could modify AD pathology and behavioral deficits in symptomatic 5XFAD mice. Four-month-old 5XFAD mice received oral MitoQ for four months, and behavioral, histological, and biochemical analyses were performed at eight months of age. MitoQ administration significantly improved novelty-related exploration, attenuated hyper-locomotor activity, and broadly suppressed amyloid pathology, including pan-Aβ, oligomeric Aβ species, fibrillar plaques, and mature amyloid deposits across the cortex, hippocampus, thalamus, and amygdala. MitoQ also attenuated astrocyte and microglial reactivation, reduced pathological pTau622, and preserved neuronal integrity. Restoration of mitochondrial homeostasis was reflected by increased PDH-positive mitochondrial particle area, reduced oxidative DNA damage, and normalization of mitochondrial clearance via restoration of mitophagy-associated quality-control markers. Collectively, these findings show that MitoQ administration was associated with improvement in mitochondrial redox- and quality-control-related indices, accompanied by reductions in amyloid burden, gliosis, and neuronal injury in animals with established AD pathology. These findings support mitochondrial redox homeostasis as a therapeutically relevant target that may influence multiple pathological features of AD and provide a preclinical rationale for further evaluation of MitoQ as a potential therapeutic strategy for AD. Given that MitoQ has been evaluated in clinical studies in other conditions, the present preclinical findings support further investigation of its translational potential in AD; however, its safety and efficacy in individuals with AD require direct clinical evaluation.

DOI: https://doi.org/10.14336/AD.2026.0946
J Nutr Metab. 2026 ;2026 5589963

A Randomized, Double-Blind, Placebo-Controlled Trial Comparing the Effects of Commercially Available Ubiquinone, Ubiquinol, and Geranylgeraniol Dietary Supplements on Plasma CoQ10 Concentrations.

Christopher R D'Adamo, Michelle Leary, Christopher Mote, Ronald Ackerman, Mark Holthouse, Brandilyn Binstock, Ellie Adair, Gabriela Piedrahita, Scott Wehage, Kristine Burke.

   Background: Coenzyme Q10 (CoQ10) plays a fundamental role in energy production and antioxidant activity in humans. Direct supplementation with both the ubiquinol and ubiquinone forms of CoQ10 increases circulating concentrations, although comparative efficacy remains uncertain. Furthermore, nutrients supporting endogenous CoQ10 production, such as geranylgeraniol (GG), suggest that supplementation may indirectly increase CoQ10 concentrations.
Methods: A randomized, double-blind, parallel-arm, placebo-controlled trial was conducted comparing 8 weeks of label-dose supplementation with commercially available formulations of (1) ubiquinone; (2) ubiquinol; (3) GG; (4) ubiquinol + GG; and (5) placebo among healthy adults. The primary outcome was plasma CoQ10 concentrations. Secondary outcomes included lipid concentrations, markers of kidney and liver function, and validated questionnaires (PROMIS-Global Health, Profile of Mood States-Vigor subscale, and SF-36 Vitality subscale) assessing physical and mental health. Mean changes were compared across study arms using analysis of covariance (ANCOVA). Bonferroni correction for multiple comparisons was applied to the comparisons to placebo, and statistical significance was set at p < 0.0125. Tukey's multiple comparison procedure was applied to comparisons between each of the active study products, and statistical significance was set at p < 0.05.
Results: A total of 150 participants were randomized. The mean age was 52.1 years, and the sample was diverse with respect to sex and race/ethnicity. Changes in CoQ10 with ubiquinone (+ 1.46), ubiquinol (+ 2.29), and ubiquinol + GG (+ 2.45) were greater than placebo (p < 0.0001). There were no differences between GG and placebo, ubiquinone and ubiquinol, or ubiquinol and ubiquinol + GG (p ≥ 0.15). Ubiquinol + GG (+ 0.99 mg/L) outperformed ubiquinone (p = 0.045). There were no differences versus placebo in questionnaires (p > 0.16). Adverse events were rare across all study arms.
Conclusions: Supplementation with ubiquinone, ubiquinol, and ubiquinol + GG was well-tolerated and increased CoQ10 concentrations among healthy adults. While GG had no independent effects on CoQ10 concentrations, an interaction effect cannot be excluded, and this should be evaluated in a future factorial trial specifically designed for this purpose. Future studies evaluating the impact of ubiquinone + GG may also be warranted. Trail Registration: ClinicalTrials.gov: NCT06640465.

Keywords:  coenzyme Q10; geranylgeraniol; ubiquinol; ubiquinone

DOI:  https://doi.org/10.1155/jnme/5589963
Ageing Res Rev. 2026 Sep 26. pii: S1568-1637(26)00377-6. [Epub ahead of print]123 103385

Neuroenergetic flexibility in the aging brain: Cellular mechanisms and diet-induced metabolic switching.

P Balaji, Joel Mart Elias, B Kumudhaveni, R Senthilraj, G Gobinathan, M Thirumal.

  The aging brain undergoes progressive alterations in energy metabolism that may reduce its capacity to match energy supply with changing functional demands. Declining glucose metabolism, mitochondrial dysfunction, and altered neuron-glia and neurovascular interactions may contribute to this vulnerability, but these changes do not necessarily indicate complete loss of metabolic capacity. Neuroenergetic flexibility refers to the capacity to coordinate changes in substrate utilization with energetic demand while maintaining cellular and functional homeostasis. This review synthesizes evidence from cellular, animal, imaging, and clinical studies to examine the mechanisms underlying this capacity, how it changes with aging, and whether diet-induced metabolic switching can enhance it. Particular attention is given to the distinction between metabolic switching, defined as a change in the relative contribution of available substrates, and neuroenergetic flexibility, which requires coordinated adaptation across substrate delivery, cellular metabolism, mitochondrial processing, neurovascular support, and functional demand. Evidence indicates that ketogenic diets, intermittent fasting, and caloric restriction can alter substrate availability and utilization and can engage mitochondrial, cellular stress-response, and nutrient-sensing pathways. However, the strength of evidence differs across biological levels: changes in alternative-substrate utilization are more consistently demonstrated than coordinated improvements in mitochondrial, vascular, cellular, and functional outcomes. Thus, increased ketone utilization or other metabolic shifts should not, by themselves, be interpreted as evidence of restored neuroenergetic flexibility. Instead, the available evidence suggests that aging may preserve individual metabolic capacities while reducing the coordination and reserve required to adapt effectively to changing energetic demands. Dietary interventions therefore provide useful models for testing metabolic adaptability, but their ability to restore integrated neuroenergetic flexibility in aging or neurodegenerative disease remains uncertain and appears to depend on age, metabolic state, disease context, intervention characteristics, and adherence.

Keywords:  Brain aging; Glucose hypometabolism; Intermittent fasting; Ketone metabolism; Metabolic switching; Mitochondrial function; Neuroenergetic flexibility

DOI:  https://doi.org/10.1016/j.arr.2026.103385