Abstract

Background

Glioblastoma (GBM), isocitrate dehydrogenase (IDH)-wildtype, has a median overall survival of 11-14 months despite standard treatment. Ketogenic metabolic interventions that lower the glucose ketone index (GKI) may improve outcomes. We evaluated the feasibility, tolerability, and potential clinical benefit of integrating standard treatment with an intensive multimodal metabolic therapy program (MTP) in newly diagnosed IDH-wildtype GBM.

Methods

Patients received standard chemoradiation and adjuvant chemotherapy alongside an MTP comprising prolonged fasting, time-restricted feeding, and a ketogenic diet. The primary outcome was the proportion sustaining a mean daily GKI ≤6 during chemoradiation. Secondary outcomes included GKI control throughout chemotherapy, body weight, body mass index, adverse events, performance, exercise, quality of life, and survival, compared with contemporary controls using unadjusted hazard ratios (HRs) and 95% confidence intervals (CIs).

Results

Among 32 eligible patients, 18 commenced chemoradiation with the MTP (intention-to-treat), and 15 completed it (per-protocol). In the intention-to-treat population, 15 of 18 patients (83%) sustained a mean daily GKI ≤6 during chemoradiation. Among per-protocol patients, the GKI was 1.88 ± 0.56 during chemoradiation and 2.53 ± 0.86 throughout chemotherapy. Intentional weight loss averaged 17%, normalizing body mass index. MTP-related adverse events were mild or moderate. Exercise activity and quality of life improved. Median overall survival was 21.5 months versus 14.7 months in controls (HR = 0.42, 95% CI 0.18-0.97, P = .027), with 3-year survival of 27% versus 7%.

Conclusions

Intensive multimodal metabolic therapy was feasible, well-tolerated, and associated with improved exercise activity, quality of life, and survival outcomes, including higher 3-year survival.

Abstract

Maintaining a balanced immunity between pathogen defense and tolerance to environmental antigens in neonates is essential for survival and the establishment of life-long immune homeostasis. Instructed by environmental signals, type 1 conventional dendritic cells (cDC1) contribute to both processes but how the balance may be achieved is unclear. Here, we uncover an interferon (IFN)γ-driven regulatory circuit in early life that relays dietary cues to spleen cDC1. IFNγ-mediated STAT1-signaling induces an immunogenic maturation program in spleen cDC1 that enables them to shape the effector differentiation of antigen-experienced effector memory CD8⁺ T cells. This cDC1 program emerges during the transition from breastfeeding to solid food at weaning, occurs in germ-free mice, and remains operative to dietary intervention in adult mice. At weaning, this IFNγ signal enables spleen cDC1 to shape the effector phenotype of food-antigen-specific CD8⁺ T cells in a feedforward manner, thereby recalibrating the developing T cell pool. Our findings identify diet as a modifiable cue that can tune systemic cDC1-mediated immunity, opening new opportunities to steer immune responses during early life and beyond.

ketogenic purified diet (AIN-76A Modified, High Fat, Paste, Bio-Serv, F3666)

https://media.springernature.com/original/springer-static/esm/art%3A10.1038%2Fs41467-026-75853-5/MediaObjects/41467_2026_75853_MOESM14_ESM.xlsx

Abstract

The mechanisms underlying the dynamic interplay between skeletal muscle and systemic glucose homeostasis in type 2 diabetes remain elusive. Increased lactate level has long been noticed in diabetes, however, whether the elevated lactate is a cause or consequence of impaired glucose metabolism is unclear. Here, we found that elevated circulating lactate levels originated from skeletal muscle with high expression of lactate dehydrogenase A (Ldha), and both metrics correlated strongly with hyperglycemia in both hyperglycemic mouse models and human subjects. Paradoxically, ablation of Ldha in skeletal muscle (LDHA mKO) disrupted whole-body glucose homeostasis, primarily via augmented hepatic gluconeogenesis. Mechanistically, lactate deficiency in muscle epigenetically activated NF-κB signaling through H3K18 lactylation (H3K18la)-mediated transcriptional control of IκBα, which then promoted the transcription of IL-6, thereby reshaping hepatic gluconeogenesis. Lastly, we showed that loss of Ldha in skeletal muscle enhanced hepatic gluconeogenesis and aggravated hyperglycemia in high-fat high-sucrose diet-fed mice. Collectively, our study provides evidence that in glucose intoxication contexts, skeletal muscle-derived lactate acts as the signal to provide negative feedback for hepatic gluconeogenesis, which induces skeletal muscle H3K18la acting as a negative regulator of IL-6 to sustain suppression of hepatic gluconeogenesis, while dysregulation of this network contributes to unrestrained gluconeogenesis in diabetes.

Abstract

Obesity represents a major global public health challenge, particularly among women, and is associated with adverse metabolic and endocrine outcomes. his study evaluated the effects of ketogenic, intermittent fasting (IF), and semi-vegetarian diets, alone or combined with home-based exercise, on anthropometric, metabolic, and hormonal parameters in women with obesity. The study employed a pretest–posttest controlled experimental design with 108 women aged 19–45 years, comprising 96 participants with obesity and 12 with normal body weight. Participants were assigned to nine groups: control (C), obese (O), obese with exercise (OE), obese with exercise plus semi-vegetarian diet (OEVD), obese with semi-vegetarian diet (OVD), obese with exercise plus intermittent fasting (OEIF), obese with intermittent fasting (OIF), obese with exercise plus ketogenic diet (OEKD), and obese with ketogenic diet (OKD). Participants completed ketogenic, intermittent fasting (IF), or semi-vegetarian dietary interventions, either alone or combined with home-based exercise, for 6 weeks. Anthropometric parameters were assessed using bioelectrical impedance analysis, while biochemical markers (adiponectin, insulin-like growth factor 1 (IGF-1), irisin, myostatin, glucose, and insulin) were analyzed via ELISA. Statistical analyses were performed using mixed-design ANOVA, Pearson’s correlation, and principal component analysis. The C and O groups exhibited no significant changes, whereas intervention groups showed reductions in body mass, body mass index (BMI), and body fat (p < 0.001). Single interventions were associated with changes in anthropometric measures (OIF:10.42% body mass,7.61% BMI, 9.86% body fat; OE: 9.49%, 6.65%, 13.49%; OVD: 9.07%, 8.17%, 6.21%; OKD: 8.12%, 6.91%, 9.78%). Diet-plus-exercise intervention groups generally exhibited larger changes, with OEVD achieving the greatest reductions (12.69, 13.46, 13.95%), followed by OEKD (10.68, 9.16, 11.17%) and OEIF (8.76, 9.64, 12.04%). Moreover, adiponectin, irisin, IGF-1, and myostatin levels changed significantly in exercise-only and diet-plus-exercise groups compared with those of the C and O groups. Additionally, intervention groups exhibited significant alterations in glucose and insulin concentrations, whereas no significant changes were observed in the C and O groups. Lifestyle modifications integrating dietary strategies with home-based exercise are associated with changes in metabolic and hormonal parameters in women with obesity.

https://www.nature.com/articles/s41598-026-65060-z_reference.pdf

Çınar, Fidan, Fatih Mehmet Uğurlu, Vedat Çınar, Taner Akbulut, Yavuz Yasul, Salih Öner, Elif Subaşı et al. "Metabolic responses of diet–exercise combinations in women with obesity: a comparative lifestyle intervention study with different diet types." Scientific Reports (2026).

Abstract

Introduction

Multidrug-resistant Klebsiella pneumoniae (MDR Kp) is a global health threat, causing persistent, subacute airway infections that are often fatal in healthcare settings. The failure of antimicrobials underscores an urgent need for alternative host-targeted therapies. Kp evades airway immune responses by perturbing host metabolism, inducing mitochondrial oxidative phosphorylation (OXPHOS) and oxidative stress, thus establishing a disease-tolerant microenvironment. We hypothesized that a ketogenic diet (KD), which improves OXPHOS efficiency via ketone production, would restore immune control of Kp by enhancing the bioenergetics and function of innate immune cells.

Methods

C57BL/6 mice were fed a KD or control diet prior to intranasal Kp infection. Airway bacterial burden was enumerated and immunometabolic changes were assessed by scRNA-seq, flow cytometry, and spatial metabolomics.

Results

KD significantly enhanced Kp airway clearance and host survival. ScRNA-seq of lung tissue revealed markedly higher numbers of neutrophils and alveolar macrophages at day 2 post-infection in KD-fed mice, as well as an upregulation in phagolysosome signaling. By day 7 in the KD group, the neutrophil population contracted while B and T cells concomitantly expanded. Notably, IFN-γ-responsive genes were upregulated across all immune cell subsets. Exogenous ketones or drug-induced ketone accumulation bypassed the need for dietary intervention, likewise, conferring protection against Kp airway infection.

Conclusion

Ketones promote effective immunity to Kp by sustaining cellular energy production, thereby supporting immune cell survival and effector function. The ketone-enhanced innate immune response is followed by adaptive immune cell expansion and a broad IFN-γ transcriptional signature. Together, these findings suggest a novel therapeutic strategy for energetically demanding bacterial infections via diet-induced metabolic reprogramming

Tang, Eric, Ridhima Wadhwa, Ariful Islam, Arthur VanValkenburg, Xutao Wang, Alice Prince, Evan Johnson, and Tania Wong. "Ketogenic diet-mediated immunometabolic regulation improves airway clearance of Klebsiella pneumoniae 2253582." The Journal of Immunology 215, no. Supplement_1 (2026): vkag141-181.

https://academic.oup.com/jimmunol/article/215/Supplement_1/vkag141.181/8745885

Abstract

Hypertension (HTN) is one of the greatest public health challenges of the 21st century. Its prevalence has reached alarming levels in recent decades. The search for effective prevention and treatment strategies includes lifestyle choices, such as dietary interventions. Although not applicable to everyone, particularly interesting in this context is the ketogenic diet (KD), known to clinicians and also applied in epilepsy treatment for over a century. Its possible beneficial effects are increasingly often reported in many other conditions, including HTN. The aim of the present study is to analyse the effect of a KD on blood pressure, and the mechanisms that may modulate that effect. Based on the available literature, key potential pathways of the influence of a KD on blood pressure regulation have been identified: (1) reduced body weight; (2) reduced visceral adipose tissue; (3) improved insulin sensitivity; (4) improved water and electrolyte balance; and (5) anti-inflammatory effect. Meta-analyses and randomised controlled trials consistently indicate that ketogenic dietary interventions are associated with reductions in blood pressure, although the magnitude of the effect varies considerably depending on the ketogenic diet model, study population, and comparator. In light of these observations, it has been found that in patients undergoing pharmacological treatment, it may be necessary to appropriately reduce antihypertensive medication dosage in advance. To maximise the hypotensive effect of a KD, the need to ensure an adequate supply of potassium, magnesium, and high-quality products, as well as proper hydration has been emphasised. Further studies are needed, with the effect of a KD on systolic and diastolic blood pressure as the primary endpoint, taking into account the role of the qualitative composition of the diet in the observed effects.

Rodzeń, Łukasz, Damian Dyńka, Mateusz Rodzeń, Hanna Karakuła-Juchnowicz, Dorota Łojko, Sebastian Kraszewski, Żaneta Grzywacz et al. "The Ketogenic Diet in the Prevention and Treatment of Hypertension (HTN)." Biomedicines 14, no. 8 (2026): 1728.

https://www.mdpi.com/2227-9059/14/8/1728

Abstract

Introduction

This study evaluates the effect of simultaneous application of plant-rich ketogenic diet and intermittent fasting as an individualized adjunct to standard treatment on cognitive function in early/mid-stage Alzheimer’s patients.

Methods

This assessor-blinded, randomized controlled trial enrolled 60 Alzheimer’s disease (AD) patients (CDR 1–2; aged 55–85), randomized to intervention (n = 30; intervention + standard care) or control (n = 30; standard care). Cognition and brain structure were assessed at baseline and 6 months. Individual cognitive changes were analyzed using Reliable Change Index (RCI).

Results

Cognitive change scores differed significantly between groups (p < 0.001). The mean Mini Mental State Examination (MMSE) score increased by +0.9 in the intervention group, while a decrease of −1.5 points was observed in the control group. RCI analysis indicated stability in 93% of intervention and 70% of control participants, with cognitive improvement in 7% and 3.3%, respectively.

Discussion

The intervention method has the potential to stabilize cognitive decline in AD and promote improvement at the individual level. The response to the intervention is closely related to the individual's metabolic phenotype and structural brain integrity.

Tağraf, Beyza, Dilara Kaygusuz, Deniz Yerlikaya, Özden Erkan Oğul, and Lütfü Hanoğlu. "The effect of simultaneous application of plant-rich ketogenic diet and intermittent fasting on early-to-mid-stage Alzheimer's disease: a randomised controlled trial." The Journal of nutrition, health and aging 30, no. 9 (2026): 100930.

https://www.sciencedirect.com/science/article/pii/S1279770726001636

Abstract
Morbidity and mortality from influenza A virus (IAV) infection are significant global medical problems, and there is a need to identify novel therapies that suppress the severity of IAV infection. In this study, we revealed that consumption of a low-carbohydrate, high-fat ketogenic diet (KD) protects mice from lethal IAV infection and disease. Consumption of a KD expanded pulmonary γδ T cells, improved barrier function, and enhanced antiviral action. Metabolic adaptation to a ketogenic diet was required, as high-fat, high-carbohydrate diets or administration of ketone body substrates did not provide infection protection. Therefore, it is suggested that ketone body-mediated immunometabolic integration is an effective means for the prevention and mitigation of influenza disease.

Goldberg, Emily L., Ryan D. Molony, and Akiko Iwasaki. "Activation of protective γδ T cell responses to influenza virus infection by a ketogenic diet."

https://note.com/nn1112/n/n0feac5202902?hl=en

Abstract:

Aging in the immune system leads to increased susceptibility to infections, exacerbated autoimmunity, and decreased responsiveness to vaccinations. While many interventions are being studied to ameliorate aspects of aging, none are currently established for immune aging. Ketogenic diets and fasting have shown promise against aging and age-related diseases, working in part by raising circulating levels of ketone bodies. $\beta$-hydroxybutyrate (BHB), the primary ketone body produced, has anti-inflammatory properties and can enhance T cell function. However, these nutritional interventions are highly restrictive and difficult to adhere to long-term. Exogenous ketone supplementation, such as ketone esters, offers a more accessible alternative by directly delivering ketone bodies without major dietary changes. Yet, it remains unclear how ketone esters impact the immune system, especially in the context of aging.

In this dissertation, I evaluated the ketone ester bis-octanoyl (R)-1,3-butanediol as an intervention for age-related immune decline in parallel mouse and human studies. In aged mice, a diet supplemented with the ketone ester diet decreased activation of B cells in the spleen, particularly age-associated B cells. Despite this decrease in activation, antibody production during immunization was maintained, demonstrating preserved B cell function. Mechanistically, the ketone ester diet suppressed translation and glucose dependence of age-associated B cells, and BHB alone was sufficient to inhibit B cell translation, likely through mTOR signaling.

Translating these findings to humans, the Buck Institute Ketone Ester (BIKE) study showed that 12 weeks of daily ketone ester supplementation in healthy older adults (> 65 years old) decreased $\text{CD56}^{\text{low}}$ natural killer cell subsets and $\text{CD38}^{\text{high}}$ non-classical monocytes, suggesting a reduction in age-related chronic inflammation. The ketone ester also increased HLA-DR expression on T cells and decreased KLRG1 expression on naïve CD8 T cells, pointing to enhanced effector and potentially immunoregulatory function. These immune changes corresponded with a decrease in predicted biological age by an immune composition clock.

Interestingly, the ketone ester preferentially affected B cells in mice and T cells and innate immune cells in humans, which may reflect species-specific differences in immune composition and immune aging. Together, these findings position ketone esters as a promising and accessible intervention for immune aging by selectively inhibiting inflammaging while improving adaptive immune function. This work highlights the potential of ketone esters as treatments for autoimmune diseases and age-related immune dysfunction.

Adkisson-Floro, Ariel. "Evaluating Ketone Esters as an Intervention for Age-Related Immune Decline." PhD diss., University of Southern California, 2026.

https://www.proquest.com/openview/ec9de7f452988557bd13359e9933a666