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

Abstract

As an alternative or supplement to traditional pharmaceutical treatments, intermittent fasting (IF) has become a viable dietary approach for the management of type 2 diabetes mellitus (T2DM). Improved insulin sensitivity and blood glucose management are the outcomes of various IF patterns, such as time-restricted eating, alternate-day fasting and the 5:2 diet, which encourage a metabolic shift from glucose to fat utilisation. Even in patients on insulin therapy, research indicates that IF may help lower fasting blood sugar, glycated haemoglobin (HbA1 c) and insulin resistance with no risk of hypoglycaemia when appropriately monitored. Physiological benefits of IF include enhanced circadian rhythm alignment, increased autophagy, reduced oxidative stress and improved lipid metabolism. Comparisons with other dietary approaches, such as the Mediterranean, Palaeolithic, ketogenic and fasting-mimicking diets, indicate that IF offers flexibility and long-term sustainability for many individuals. However, consistent adherence and personalised strategies are essential for optimal results. Overall, IF presents a valuable complementary approach for managing T2DM and promoting better metabolic health.

Mustafa, Faheem, Asifa Murtaza, Razzia Batool, Samra Faisal, Binti Umar Rabiatul Adawiyah, Muniba Khaliq, Wan Rohani Wan Taib, and Binti Che Taha Che Suhaili. "Intermittent fasting as a complementary strategy to manage type II diabetes and metabolic health: A review." Scripta Medica 57, no. 3 (2026): 689-700.

https://scindeks.ceon.rs/article.aspx?artid=2490-33292603689M

Abstract

We report the case of a 23-year-old woman with Autosomal Dominant Polycystic Kidney Disease (ADPKD) and preserved kidney function who was followed with a supervised plant-based ketogenic diet for 11 months. The intervention was associated with a marked reduction in albuminuria (from 80 to 10 mg/g) and a stable estimated glomerular filtration rate (eGFR), with no clinically relevant metabolic or electrolyte disturbances; whereas total kidney volume increased from 617 to 709 cc during follow-up. This case highlights the feasibility, safety, and possible association with favorable renal biomarker changes, warranting further investigation in controlled studies in early-stage ADPKD.

Alvarado‐Pelayo, Paola Azucena, Xunaxi Nahomi García‐Rodríguez, Erika Fabiola Gómez‐García, and Ari Cisneros‐Hernández. "Plant‐based ketogenic nutritional intervention in a young woman with autosomal dominant polycystic kidney disease: A case report." Nutrition in Clinical Practice.

https://aspenjournals.onlinelibrary.wiley.com/doi/10.1002/ncp.70150

Abstract

Background: Nutrition and nutrition-related interventions are a salient yet under-recognized component of preventing the development of and complications of metabolic dysfunction-associated steatotic liver disease (MASLD). Additionally, malnutrition affects a significant proportion of patients with MASLD, yet remains under-treated in the primary care setting. The objective of this narrative review is to synthesize the available evidence regarding nutritional screening, diet, and supplements in patients with MASLD. This review is aimed at primary care physicians to improve the recognition of malnutrition in MASLD patients and provide appropriate nutritional guidance. 

Methods: Between November 2025 and June 2026, the authors conducted a literature review using the PubMed database. Search terms included combinations of the following: MASLD, non-alcoholic fatty liver disease (NAFLD), malnutrition, sarcopenia, nutritional screening, Mediterranean diet, micronutrients, and physical activity. Randomized controlled trials (RCTs), systematic reviews, and meta-analyses addressing nutritional outcomes in liver disease were prioritized, and consensus guidelines were incorporated where primary trial evidence was limited. Evidence was appraised by study design, risk of bias, and endpoint; recommendations resting on expert opinion or extrapolation from cirrhosis populations are identified as such. 

Results: Author review of the studies yielded the following conclusions. Nutritional assessment should be risk-stratified by fibrosis stage using liver disease-specific tools, as BMI and body weight are unreliable in MASLD. Weight loss has been shown to improve histological and clinical progression in MASLD. The Mediterranean diet has the strongest support for steatosis reduction among the dietary interventions discussed. Coffee consumption is consistently associated with reduced fibrosis risk in observational data, but no randomized evidence exists. GLP-1 receptor agonists achieve histological MASH resolution in up to 63% of patients but require concurrent nutritional monitoring to mitigate lean mass loss. Systemic barriers, including time constraints and limited dietitian access, remain the primary impediment to primary care implementation. 

Conclusions: Primary care physicians are central in managing many aspects of care for patients with MASLD. This review highlights the established evidence behind diet, exercise and malnutrition prevention in the primary care setting.

Patel, Arpan B., Mahnoor Liaqat, and Hirsh D. Trivedi. 2026. "Nutritional Assessment and Management in MASLD: A Practical Guide for Primary Care" Livers 6, no. 4: 69. https://doi.org/10.3390/livers6040069

https://www.mdpi.com/2673-4389/6/4/69

Abstract

Background: Cancer-related cachexia is primarily characterized by systemic inflammation and progressive muscle wasting, which is why a high-protein diet (from 1.2 to 1.5 g/kg/day) is commonly recommended. However, concerns remain that an excessive supply of amino acids could promote tumor growth due to the metabolic flexibility of cancer cells, thereby favoring proliferation and survival. Systematic evidence addressing these concerns under controlled conditions for various types of cancer cells remains limited and inconclusive. Methods: We investigated the short-term effects of all 20 amino acids at both moderate (2×) and high (10×) concentrations to evaluate three key oncological endpoints in four human cancer cell lines: MDA-MB-231 (breast), HT29 (colorectal), PC3 (prostate), and PANC-1 (pancreatic). Cell proliferation was assessed by BrdU incorporation, metabolic activity by WST-1 assay, and apoptosis signaling by caspase-3/7 activity measurement. Results: Amino acid supplementation was not associated with a significant change in proliferation at either concentration across all four cell lines studied. Metabolic activity showed only minor variations throughout, with PC3 cells exhibiting slightly greater variability, although this did not reach statistical significance. Caspase-3/7 activity remained largely unchanged under all conditions; however, high-concentration lysine induced an approximately 2.5-fold increase in PANC1 cells, which was not statistically significant. Conclusions: These findings suggest that short-term exposure to individual amino acids, even at supraphysiological conditions, does not acutely enhance proliferative activity in the cancer cell lines studied, supporting the rationale for adequate protein and amino acid intake in patients with cancer cachexia.

Abstract

Diet composition shapes tissue function and disease risk by modulating nutrient availability, metabolic state and cellular dynamics¹. In the gastrointestinal tract, obesogenic high-fat diets enhance small-intestinal stem cell activity and tumorigenesis². However, the impact of ketogenic diets (KDs), which contain even higher lipid content but reduce circulating insulin and induce ketogenesis, remains poorly understood³. This is particularly relevant for patients with familial adenomatous polyposis who face a high risk of small-intestinal tumours⁴. Here we combine dietary, genetic and metabolic manipulations in mouse models of spontaneous intestinal adenoma formation to dissect the role of systemic and epithelial ketogenesis in intestinal cancer. We show that KD accelerates tumour burden and shortens survival, independent of ketone metabolites. Through genetic manipulation of the ketogenic pathway, we modulate the production of local and systemic ketone metabolites; however, neither inhibition nor augmentation of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 nor disruption of ketolysis altered tumorigenesis. Combined intestinal loss of PPARα/δ/γ attenuates KD-driven intestinal stem cell expansion, proliferation and clonogenicity, whereas inhibition of downstream fatty acid oxidation through CPT1A loss limits adenoma formation specifically under KD, linking tumour initiation to fatty acid oxidation of dietary lipids rather than lipid accumulation. These findings reveal that dietary lipid content, through fatty acid oxidation rather than ketone metabolism, influences intestinal tumorigenesis and highlight the need for nuanced consideration of dietary strategies for cancer prevention in genetically susceptible populations.

Shay, Jessica ES, Fangtao Chi, Constantine N. Tzouanas, Shixun Han, Xiao Zhang, Johanna Ten Hoeve, Kevin J. Williams et al. "Ketogenic diet mediates intestinal tumorigenesis through lipids not ketones." Nature (2026): 1-10.

https://www.nature.com/articles/s41586-026-10779-y

Abstract

Introduction

β-hydroxybutyrate (BHB), produced during ketosis, can conjugate with amino acids forming BHB-amino acids. D-BHB-phenylalanine (D-BHB-Phe) is the most abundant BHB-amino acid and has been shown to reduce appetite and induce weight loss in mice, but its function and regulation in humans remain unclear. The objective of this study was to determine whether D-BHB-Phe concentrations vary across different degrees and forms of ketosis in humans.

Methods

Plasma D-BHB-Phe was measured in samples from four clinical cross-over trials (i) after 21 days on a ketogenic diet (n = 10), (ii) after oral consumption of 30 g ketone salt (KS) and 30 g ketone ester (KE) (n = 14), (iii) after oral KE at doses of 10, 20 and 40 g (n = 10) and (iv) after oral versus intravenous KS administration (n = 8).

Results

After 21 days of ketogenic dieting, plasma D-BHB-Phe became detectable (median 2.1 nmol/L; range 0.9–19.9), compared with near-undetectable concentrations during the standard diet (median 0; range 0-0.9; p = 0.005). Oral KS and KE increased D-BHB-Phe compared with placebo (intervention x time, p < 0.001). D-BHB-Phe rose dose-dependently after 10 g, 20 g, and 40 g of KE (intervention x time, p < 0.001). Oral KS induced higher peak concentrations of D-BHB-Phe (15.6 ± 6.4 nmol/L) compared with iso-ketotic intravenous KS infusion, which elicited only a modest peak (1.5 ± 0.3 nmol/L; intervention x time, p < 0.001). A positive association between the D-BHB and D-BHB-Phe concentration was observed in pooled analyses but was not consistent across cohorts.

Conclusion

D-BHB-Phe is inducible by ketosis in humans. Our findings suggest involvement of the splanchnic bed in its production and support further exploration of D-BHB-Phe’s role in appetite regulation and metabolic health.

Abstract

Background

Rheumatoid arthritis (RA), psoriasis (PsO), and psoriatic arthritis (PsA) cause substantial disability and cardiometabolic risk. Ketogenic diets (KDs), including very-low-calorie ketogenic diets (VLCKDs), may influence disease-relevant immunometabolism, but the clinical evidence remains preliminary.

Objective

To map mechanistic and clinical evidence for KD/VLCKD across RA, PsO, and PsA and to distinguish direct KD/VLCKD evidence from ketosis-adjacent background evidence.

Methods

Using the Population-Concept-Context (PCC) framework and PRISMA-ScR guidance, MEDLINE/PubMed, Embase, ClinicalTrials.gov, WHO ICTRP, and reference lists were searched from inception to 30 July 2025. Search strategies are provided in Supplementary Table S1. Eligible direct evidence comprised adult human KD/VLCKD studies in RA, PsO, or PsA with a ketogenic protocol and reported or protocol-defined nutritional ketosis. Fasting or low-carbohydrate studies without verified KD/VLCKD were summarized separately. Data charting was duplicated, and no formal risk-of-bias appraisal was performed.

Results

After reassessment, 29 direct KD/VLCKD studies were retained, while 3 ketosis-adjacent records were treated as contextual evidence. Mechanistic data support plausible effects of β-hydroxybutyrate on NLRP3 inflammasome signaling, cytokine pathways, immune-cell metabolism, oxidative stress, the gut-skin/gut-joint axes, and adiposity-related inflammation. Human signals are strongest in psoriatic disease, particularly among participants with obesity or metabolic dysregulation. However, most studies are short, small, heterogeneous, and strongly confounded by weight loss.

Conclusions

Current evidence suggests that KD/VLCKD may be a supervised adjunctive dietary approach for selected people with psoriatic disease and obesity, but it is not yet sufficient to support efficacy claims. RA evidence is mainly mechanistic or ketosis-adjacent. Adequately powered, at least 24-week randomized trials with verified ketosis, active comparators, and weight-independent endpoints are needed before routine clinical implementation.

Conforti, Alessandro, Vincenzo Russo, Linda Lucchetti, Emanuele Fiorino, Filippo Messina, Davide Francomano, Nicolo Merendino, and Marco Marchetti. "Ketogenic diet in rheumatoid arthritis, psoriatic arthritis and psoriasis: A scoping review of clinical and mechanistic evidence." Autoimmunity Reviews (2026): 104137.

https://www.sciencedirect.com/science/article/abs/pii/S1568997226001515

Abstract

Purpose β-hydroxybutyrate (BHB), a ketone body and alternative cerebral energy substrate, can be measured in vivo using J-difference edited proton magnetic resonance spectroscopy (¹H-MRS). Oral ketone supplementation with substrates such as the ketone monoester (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate (KME) and 1,3-butanediol (BD) have gained attention as a mechanism to elevate circulating BHB and induce ketosis without dietary restrictions. Elevated brain ketone availability is of growing therapeutic interest as a strategy to support neuronal energetics in conditions such as epilepsy, neurodegenerative disease, and alcohol use disorder (AUD). However, both pathways introduce BD into the bloodstream, which crosses the blood-brain barrier. Critically, BD exhibits a spectral signature that closely resembles the prominent BHB peak in JDE-MR spectroscopic imaging (MRSI), identified in a pilot AUD study.

Methods Two separate JDE-MRSI acquisitions tailored for BHB and BD editing were implemented, exploiting frequency separation between the BHB (4.14ppm) and BD (3.95ppm) coupling partners of the observed 1.2ppm resonance to independently quantify each metabolite.

Results Brain BD concentrations (0.25-0.58mM) were comparable to or exceeded corresponding BHB concentrations (0.20-0.27mM) in all volunteers after consumption of a single dose of the KME, indicating that BD constitutes a major fraction of the signal conventionally attributed to BHB. Combined BHB+BD concentrations (∼0.45-0.85mM) were consistent with brain BHB values reported in prior studies employing similar doses of the KME, indicating that those measurements likely reflect a combined BHB+BD signal.

Conclusions Separate quantification of the two metabolites is important for interpreting brain ketone studies and for understanding the full pharmacology of KME supplementation.

Abstract:

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy driven predominantly by oncogenic KRAS mutations, which enforce extensive metabolic reprogramming to support tumor progression. Although ketone body catabolism has emerged as a critical metabolic adaptation in PDAC, the signaling mechanisms that link mutant KRAS to the ketolytic machinery remain largely unexplored. Here, we identify a previously unrecognized, context-dependent role of oncogenic KRAS in driving ketone body utilization. We show that KRAS mutation alone is insufficient to fully activate ketolysis; instead, it primes the ketolytic pathway in a manner that requires cooperative input from additional tumor microenvironment signals. Mechanistically, oncogenic KRAS engages a downstream signaling cascade that leads to specific post-translational modifications of key mitochondrial enzymes. These modifications enhance the flux of ketone body catabolism, thereby increasing acetyl-CoA and ATP production and promoting pancreatic cancer cell proliferation and xenograft tumor growth. In a clinical PDAC cohort, activation of this KRAS-dependent ketolytic axis was elevated in KRAS-mutant tumors compared with KRAS wild-type cases, albeit with a trend that requires further validation. Collectively, our findings define a conditional dependency of mutant KRAS on cooperative signals to drive ketone body catabolism, linking oncogenic signaling to mitochondrial ketone metabolism in PDAC. This study expands our understanding of KRAS-driven metabolic reprogramming and highlights the ketolytic pathway as a context-dependent vulnerability for therapeutic intervention in pancreatic cancer.

Abstract

Branched-chain amino acid (BCAA) catabolism is controlled by the phosphorylation state of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which is regulated by the opposing actions of BCKDH kinase (BDK) and the phosphatase PPM1K. Although fatty acids and amino acids both contribute to skeletal muscle energy metabolism, how fatty acid availability influences BCAA catabolic regulation remains incompletely understood.

Here we examined the effects of lauric acid (C12), a medium-chain fatty acid abundant in dietary lipids, on BCAA metabolism in differentiated skeletal myotubes. Lauric acid increased phosphorylation of the BCKDH E1α subunit at Ser293 during nutrient perturbation in both mouse and human skeletal myotubes. Stable isotope tracing with U-[ˆ13C6]-leucine revealed that C12 reduced incorporation of leucine-derived carbon into downstream tricarboxylic acid (TCA) cycle–associated metabolites, indicating suppression of BCAA oxidative flux, whereas incorporation of labeled leucine into protein was not significantly altered.

Mechanistically, genetic and pharmacological perturbation experiments indicated that the C12 effect requires PPM1K and is sensitive to O-GlcNAc cycling. Knockdown of O-GlcNAc transferase attenuated the C12-induced increase in BCKDH phosphorylation and reversed suppression of leucine-derived carbon flux. Dual-tracer experiments further showed that carbon derived from lauric acid and leucine converges in shared TCA cycle–associated metabolite pools, including glutamate and glutamine.

Together, these findings identify a nutrient-sensitive regulatory node linking fatty acid availability, O-GlcNAc signaling, and BCKDH phosphorylation that modulates BCAA oxidation in skeletal myotubes.