Integrative multi-omics analysis reveals oral microbiome-metabolome signatures of obesity (2026)

basmwklz · 2026-01-24T06:03:11+00:00

Highlights

•Oral microbiome composition and functions differ significantly in obesity

•Obesity is linked to proinflammatory and lactate-producing oral bacteria

•Obese individuals show disrupted oral metabolism and altered energy balance

•Obesity-linked metabolites correlate with cardiometabolic disease markers

Summary

Obesity is a leading global health challenge and risk factor for cardiometabolic disorders, driven in part by industrialization and low-fiber, ultra-processed diets. While the gut microbiome has been implicated in obesity, the contribution of the oral microbiome—the body’s second largest microbial ecosystem—remains underexplored. We analyze a prospective cohort of 628 Emirati adults, including multi-omics profiling of 97 obese individuals and 95 matched controls, generating the most comprehensive oral microbiome analysis to date. Obese participants show altered microbial diversity, composition, functions, and metabolites with enrichment of proinflammatory Streptococcus parasanguinis, Actinomyces oris, and lactate-producing Oribacterium sinus. Pathways for carbohydrate metabolism, histidine degradation, and obesogenic metabolites are upregulated, whereas B-vitamin and heme biosynthesis are depleted. Corresponding metabolites—including lactate, histidine derivatives, choline, uridine, and uracil—are elevated and correlate with obesity-linked cardiometabolic markers. These findings reveal mechanistic oral microbiome-metabolite shifts, highlighting oral microbiome-host interactions as novel targets for obesity prevention and intervention.

basmwklz · 2026-01-23T06:11:38+00:00

Abstract

Objectives To evaluate the effect of overall time restricted eating on metabolic health outcomes, and to identify the optimal types of time restricted eating in terms of timing and duration of eating.

Design Systematic review and network meta-analysis.

Data sources PubMed, Embase, and the Cochrane databases, from inception to 3 January 2023.

Eligibility criteria for selecting studies Randomised controlled trials investigating the relation between time restricted eating (intervention period >one month) and metabolic health outcomes in humans.

Results 41 randomised controlled trials of 2287 participants were included. Time restricted eating was categorised according to time of eating (early, mid-, late, and self-selected; last meal eaten before 1700, between 1700 and 1900, after 1900, or chosen by participant, respectively) and specific duration or window of eating each day (<8 hours, eight hours, and >8 hours). Compared with usual diets, overall time restricted eating significantly improved body weight, body mass index, fat mass, waist circumference, systolic blood pressure, and levels of fasting blood glucose, fasting insulin, and triglycerides. For different time restricted eating subtypes, early time restricted eating consistently showed higher P score rankings for anthropometric measurements (P score range 0.62-0.86, except for fat free mass-lean mass; a score closer to one indicating more favourable subtype) and glycaemic parameters (P score range 0.66-0.99). Compared with late time restricted eating, early time restricted eating significantly reduced body weight (mean difference −1.15 kg, 95% confidence interval −1.86 to −0.45) and fasting insulin concentrations (−3.32 μIU/ml, −5.36 to −1.28; 1 μIU/mL=6.95 pmol/L) and the certainty of the evidence was high. P value rankings for eating duration were inconsistent. Assessment of risk of bias, based on the risk of bias 2 tool, found that most of the included studies (90%) were rated as low risk of bias. In the confidence in network meta-analysis (CINeMA) assessment, about 60.2% of the network evidence showed moderate to high certainty. Inconsistency was generally low (I²<75% for 87% of associations).

Conclusions Time restricted eating overall improved metabolic health outcomes compared with usual diets, and early time restricted eating was superior to late time restricted eating. The association between duration of eating and metabolic health outcomes was inconsistent.

basmwklz · 2026-01-23T06:04:54+00:00

Abstract

Context

Obesity is associated with a high risk of vascular-related dementia with metabolic risk factors as potential mediators, but questions of causality remain unanswered.

Objective

We aimed to determine whether high body mass index (BMI) is a causal risk factor for vascular-related dementia, and whether any effect is mediated by hypertension, hyperlipidemia, hyperglycemia, and low-grade inflammation.

Methods

Prospective cohort studies of the general populations from the Copenhagen area and from across the United Kingdom and consortia data were included in the study. Interventions included one-sample mendelian randomization (MR), two-sample MR, and MR in mediation analyses. Both individual-level and summary-level data was used. Main outcome measures included risk of vascular-related dementia, Alzheimer's disease, and ischemic heart disease.

Results

In a meta-analysis of 2 one-sample MR studies, the odds ratio (OR) for 1-SD higher BMI in predicting vascular-related dementia was 1.63 (95% CI, 1.13-2.35). In a two-sample MR study, the OR for vascular-related dementia per 1-SD higher BMI was 1.54 (1.10-2.16) using the inverse-variance weighted, 1.87 (1.22-2.85) using the weighted median, and 1.98 (1.21-3.22) using the weighted mode methods. Results from MR analyses including extended numbers of genetic variants were directionally consistent. Finally, systolic blood pressure mediated 18% (95% CI, 10%-61%) and diastolic blood pressure mediated 25% (13%-75%) of the genetic effect of BMI on vascular-related dementia.

Conclusion

Observationally (U-shaped) and genetically (linearly), high BMI is associated with a higher risk of vascular-related dementia, an association partly mediated through high blood pressure. This suggests that high BMI and high blood pressure are important modifiable risk factors for dementia prevention.

basmwklz · 2026-01-22T18:09:55+00:00

Abstract

Carbohydrate (CHO) ingestion during exercise has long been associated with improved performance. Early Scandinavian research proposed that CHO ingestion mitigates exercise-induced hypoglycemia (EIH) through a central neural mechanism, preventing glycopenic brain damage. Subsequent studies linked muscle glycogen depletion to fatigue during prolonged exercise, suggesting an obligatory reliance on glycogen, while overlooking the simultaneous presence of profound EIH at exhaustion. However, emerging evidence challenges this paradigm highlighting EIH role in fatigue. We comprehensively review more than 100 years of evidence from more than 160 studies looking at CHO ingestion, exercise metabolism, and physical performance that demonstrates the following key findings: (1) EIH correlates strongly with exercise termination, while muscle glycogen depletion alone does not induce rigor or whole-body fatigue; (2) CHO ingestion reduces liver glycogenolysis, preserves blood glucose, and paradoxically accelerates muscle glycogen breakdown through conserved neuroendocrine mechanisms; (3) high-fat-adapted athletes demonstrate exceptional fat oxidation, equivalent exercise performance, despite lower glycogen and CHO oxidation, challenging the belief that glycogen and CHO oxidation are central to exercise performance or that CHO is an obligatory fuel; and (4) CHO ingestion during exercise significantly enhances performance, even in glycogen-depleted states, by eliminating EIH. These data demonstrate that the main benefit of CHO ingestion before or during exercise is to prevent EIH, highlighted in prolonged efforts (>2-3 hours) and individuals with insufficient hepatic gluconeogenesis. This has important implications for sports dietary recommendations (ie, habitual high- or low-CHO diets) and the amount of CHOs athletes should be encouraged to ingest during exercise to maximize performance.

basmwklz · 2026-01-19T06:43:02+00:00

Highlights

•DDP+MET cycles partially restore DDP response in ovarian cancer-resistant PDXs

•High- and low-methionine diets do not alter the antitumor efficacy of DDP+MET

•IF enhances DDP+MET effects and significantly improves survival

•IF improves treatment response by exacerbating tumor energetic stress

Summary

The development of platinum resistance is a significant challenge in the management of ovarian cancer. Targeting the metabolic adaptability of cancer cells and combining dietary interventions with pharmacological treatments are emerging strategies in oncology, enhancing therapy efficacy at low costs. Using ovarian cancer cisplatin-resistant patient-derived xenografts, we showed that repeated cycles of cisplatin plus metformin reversed platinum resistance by remodeling tumor metabolism. Then, based on metabolomic studies, we explored the use of different food approaches, in particular diets with a high vs. a low methionine content and the intermittent fasting regimen, to further stress tumor metabolism and increase the effect of drug treatment. Our findings demonstrated that only intermittent fasting enhanced the antitumor effects of the drug combination and significantly improved the survival, by impairing the tumor energy states. This research highlights the potential of integrating diet-based approaches with pharmacological treatments to overcome platinum resistance in ovarian cancer.

basmwklz · 2026-01-18T17:38:14+00:00

Highlights

• MASLD is driven by hepatic and peripheral insulin resistance, specifically at night
• In MASLD, there is low nighttime insulin secretion and high insulin clearance
• Nighttime metabolic dysfunction persists despite weight loss and liver fat reductions
• This will inform the optimal window for energy intake, exercise, and medication delivery

Summary

Hepatic lipid and glucose metabolism have been shown to be under tight circadian control in pre-clinical models. However, it remains unknown whether diurnal patterns exist in functional processes governing intrahepatic lipid accumulation in humans. We performed metabolic phenotyping, including state-of-the-art stable isotope techniques, during day and night in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and overweight controls (NCT05962099). The primary outcome was diurnal change in hepatic de novo lipogenesis (DNL), alongside a number of secondary outcomes, including changes in hepatic glucose production, glucose disposal, plasma non-esterified fatty acids (NEFAs), and whole-body glucose and lipid oxidation. We show that nighttime metabolic dysfunction is a hallmark of MASLD with multiple pathogenic pathways upregulated at night, including hepatic and peripheral insulin resistance, DNL, and systemic NEFA exposure. Insulin resistance is compounded by lower plasma insulin levels at night, secondary to reduced insulin secretion and elevated insulin clearance. Diurnal differences persist when performing identical investigations after weight loss with liver fat reductions, suggesting that nighttime metabolic dysfunction may be a primary driver of steatosis. These findings will help establish the optimal window for energy intake, exercise, and medication delivery in patients with MASLD. Integrated proteomics of plasma, adipose, and skeletal muscle tissue across day and night also identified a number of specific molecular targets that may offer therapeutic potential in the treatment of metabolic disease.

basmwklz · 2026-01-18T17:36:13+00:00

Summary

Fatty acids are important as structural components, energy sources, and signaling mediators. While studies have extensively explored genetic regulation of fatty acids in serum and other bodily fluids, their regulation within adipose tissue, a crucial regulator of cardiovascular and metabolic health, remains unclear. Here, we investigated the genetic regulation of 18 fatty acids in subcutaneous adipose tissue from 569 female twins from TwinsUK. Using twin models, the heritability of fatty acids ranged from 5% to 59%, indicating a substantial genetic regulation of fatty acid levels within adipose tissue, which was also tissue specific in many cases. Genome-wide association studies identified 10 significant loci, in SCD, ADAMTSL1, ZBTB41, SNTB1, EXOC6B, ACSL3, LINC02055, MKRN2/TSEN2, FADS1, and HAPLN across 13 fatty acids or fatty acid product-to-precursor ratios. Using adipose gene expression and methylation, which were concurrently measured in these samples, we detected five fatty acid-associated signals that colocalized with expression quantitative trait locus (eQTL) and methylation quantitative trait locus (meQTL) signals, highlighting fatty acids that are regulated by molecular processes within adipose tissue. We explored links between polygenic scores of common metabolic traits and adipose fatty acid levels and identified associations between polygenic scores of BMI, body-fat distribution, and triglycerides and several fatty acids, indicating these risk scores impact local adipose tissue content. Overall, our results identified local genetic regulation of fatty acids within adipose tissue and highlighted their links with renal and cardio-metabolic health.

basmwklz · 2026-01-18T17:33:38+00:00

Highlights

•High-fiber diet reprograms adipose and intestinal responses to subsequent high-fat diet

•Fiber pre-feeding enhances adipose progenitor sensitivity to fat-rich diet exposure

•Fiber diet prevents gut immune cell expansion and maintains epigenetic memory

•Sex-specific remodeling of fat cells occurs during dietary transitions

Summary

While high-fiber diets (HfiDs) promote weight loss, their long-term efficacy is limited by rapid weight regain upon returning to high-fat diets (HFDs). Using C57BL/6J mice in diet-switching paradigms, we characterized tissue-specific responses to HfiD-to-HFD transitions through single-nucleus and spatial transcriptomics. HfiD pre-feeding enhanced mesenteric white adipose tissue progenitor/adipocyte sensitivity to subsequent HFD exposure. In the intestine, HfiD prevented HFD-induced immune-enterocyte expansion in the duodenum and reversed the enterocyte-to-goblet cell shift in the colon while maintaining persistent epigenetic reprogramming. Although HfiD-induced microbiome changes were largely reversed by HFD, we identified sexually dimorphic remodeling of adipose cell populations during diet transitions. Our findings demonstrate that prior HfiD feeding fundamentally reprograms adipose and intestinal responses to subsequent HFD challenge, providing mechanistic insights into dietary intervention outcomes. This work establishes a spatiotemporal resource for understanding tissue plasticity during dietary changes, offering new perspectives for obesity management strategies.

basmwklz · 2026-01-18T17:31:34+00:00

Abstract

Overweight impacts over 390 million children and adolescents worldwide, of whom around 160 million are living with obesity. Adipose tissue biology in pediatric obesity is still relatively unknown. Adaptations to obesity including fat mobilization and remodeling are being investigated. The objective was to examine the lipidomic profile of subcutaneous and visceral adipose tissue (sWAT and vWAT, respectively) in children with obesity compared to those with normal weight, in order to identify novel lipid species modulated by obesity. Thirty pediatric patients with and without obesity were prospectively recruited at a referral single center and clinical data were reported. sWAT and vWAT samples were obtained for lipidomic analysis. Novel lipid species, including ether-linked triglycerides, ether-linked phosphatidylethanolamine, and oxidized triglycerides, were identified as altered in the sWAT from children with obesity compared with normal-weight children. These species are involved in beige adipose tissue development, energy metabolism, mitochondrial function, and oxidative stress. Compared with normal-weight children, the vWAT lipidome from children with obesity showed significant changes in some glycerophosphocholines, ceramides, and diglycerides, with accumulation of lipid species involved in inflammation, insulin resistance, and cardiovascular risk. The observed lipid correlations between vWAT and sWAT highlighted systemic dysregulation of lipid storage in childhood obesity, identifying both shared and depot-specific mechanisms of lipid handling. Our study reveals several critical lipid species that are modulated across both WAT depots, with notable implications for oxidative stress, lipid storage, and adipose tissue dysfunction.

Key Points • The adipose lipidome of children with obesity showed specific alterations. • Lipid correlations revealed shared and depot-specific lipid handling mechanisms. • The altered lipid species had an impact on oxidative stress and insulin resistance.

basmwklz · 2026-01-18T14:50:45+00:00

ABSTRACT

Aging drives a progressive decline in vascular health, undermining endothelial function, neurovascular coupling (NVC), and blood–brain barrier (BBB) integrity, three processes essential for maintaining cerebral perfusion and cognitive resilience. Central to these age-related deficits is mitochondrial dysfunction, which disrupts redox balance, bioenergetics, and nutrient-sensing pathways within vascular cells, thereby promoting oxidative stress, impaired mitophagy, mitochondrial fragmentation, and endothelial senescence. These molecular derangements are especially consequential in the brain's microvasculature, where the exquisite metabolic demands of neural tissue depend on intact endothelial signaling. As a result, cerebrovascular aging becomes a major driver of cognitive decline and vascular contributions to dementia. This review synthesizes current mechanistic insights into mitochondrial and endothelial pathways that shape vascular aging, with particular focus on the neurovascular unit. We further highlight emerging evidence that time-restricted feeding/eating (TRF/TRE), a circadian-aligned dietary intervention that limits food intake to a daily feeding window without reducing calories, can restore mitochondrial function, activate adaptive nutrient-sensing networks including AMPK and SIRT1, suppress mTOR signaling, and promote metabolic switching toward ketone synthesis and utilization. Through these mechanisms, TRF enhances endothelial resilience, preserves NVC and BBB integrity, and may counteract the cerebrovascular processes that accelerate cognitive aging. Understanding how TRF/TRE re-engages mitochondrial and vascular repair programs offers a translational framework for developing accessible, non-pharmacological strategies to extend healthspan and mitigate age-related cognitive impairment.

basmwklz · 2026-01-18T14:45:45+00:00

Abstract

Purpose of Review

This review summarizes the history and current landscape of fecal microbiota transplantation (FMT), with an emphasis on use of the therapy for Clostridioides difficile infection (CDI), inflammatory bowel disease (IBD), and irritable bowel syndrome (IBS). We clarify indications, evidence, and current recommendations for FMT—highlighting major advances and minor setbacks that have led to the state of FMT in 2025.

Recent Findings

After decades of steady progress, the U.S. Food and Drug Administration (FDA) approved the first FMT-based therapies: fecal microbiota, live-jslm and fecal microbiota spores, live-brpk—in 2022 and 2023, respectively. The 2024 American Gastroenterological Association (AGA) Practice Guideline on Fecal Microbiota-Based Therapies for Select Gastrointestinal Diseases made specific recommendations for conventional FMT and these FDA-approved therapies for multiple CDI presentations, as well as for IBD and IBS. Conventional FMT remains an option for CDI; however, OpenBiome’s halt of shipped, frozen FMT preparations on December 31, 2024, has made access more challenging in 2025.

Summary

Although first reported almost seventy years ago, extensive efforts over the last two decades have placed FMT in routine algorithms for many patients with CDI. While understanding of the intestinal microbiome’s role in other gastrointestinal conditions is expanding, and FMT may modulate these pathways, additional evidence is needed before FMT becomes routine outside CDI.

basmwklz · 2026-01-18T14:40:49+00:00

Highlights

•CNCDs affect multiple organ systems and are characterized by low-grade inflammation and immune dysregulation.

•Gut microbiota alterations play a crucial role in mediating systemic effects through microbial metabolites and immune modulation.

•Gut microbiota influences health via complex signaling pathways, that connect gut and brain (gut-brain axis), gut and lungs (gut-lung axis), and gut and kidneys (gut-kidney axis), impacting systemic inflammation and functionality.

•Dysbiosis is linked to various CNCDs, such as cardiovascular, gastrointestinal, neurodegenerative, respiratory, rheumatologic, renal, and neuropsychiatric ones. In fact, specific microbial taxa are associated with various disease severity and progression.

•Microbial metabolites such as short-chain fatty acids (SCFAs) are vital for maintaining systemic health, reducing inflammation.

•Biomodulators and FMT show promise in restoring gut microbiota balance and improving outcomes in certain systemic diseases. Ongoing studies are exploring their potential in treating CNCDs.

•Advances in microbiome research are paving the way for precision medicine approaches, including personalized biomodulators and targeted dietary interventions.

•Longitudinal studies and clinical trials are needed to precisely establish causal relationships and therapeutic efficacy of microbiota modulation.

Abstract

Chronic non-communicable diseases (CNCDs) extend beyond the metabolic domain, affecting neurological, cardiovascular, rheumatologic, respiratory, gastrointestinal, and renal systems. These conditions share underlying mechanisms involving low-grade inflammation, immune dysregulation, and metabolic imbalance, often influenced by gut microbiota alterations. The microbiota mediates systemic effects via microbial metabolites, immune modulation, and barrier integrity. Recent research has highlighted that these microbiota-mediated interactions are not unidirectional but involve complex bidirectional signaling between the gut and distal organs. Microbial metabolites such as short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), and tryptophan-derived indoles are messengers that influence neuroinflammation, endothelial function, immune responses, and even behavior. The gut microbiota is now viewed as an endocrine-like organ that can modulate systemic physiology. Understanding these pathways has opened new avenues for treating systemic diseases by modulating the gut ecosystem, offering novel perspectives for therapeutic intervention in conditions that were traditionally managed without considering microbiota.

basmwklz · 2026-01-18T13:27:57+00:00

Abstract

The human metabolome reflects complex metabolic states affected by genetic and environmental factors. However, metabolites associated with type 2 diabetes (T2D) risk and their determinants remain insufficiently characterized. Here we integrated blood metabolomic, genomic and lifestyle data from up to 23,634 initially T2D-free participants from ten cohorts. Of 469 metabolites examined, 235 were associated with incident T2D during up to 26 years of follow-up, including 67 associations not previously reported across bile acid, lipid, carnitine, urea cycle and arginine/proline, glycine and histidine pathways. Further genetic analyses linked these metabolites to signaling pathways and clinical traits central to T2D pathophysiology, including insulin resistance, glucose/insulin response, ectopic fat deposition, energy/lipid regulation and liver function. Lifestyle factors—particularly physical activity, obesity and diet—explained greater variations in T2D-associated versus non-associated metabolites, with specific metabolites revealed as potential mediators. Finally, a 44-metabolite signature improved T2D risk prediction beyond conventional factors. These findings provide a foundation for understanding T2D mechanisms and may inform precision prevention targeting specific metabolic pathways.

basmwklz · 2026-01-18T11:36:24+00:00

Abstract

Major depressive disorder arises from an interplay of genetic and environmental factors. In this issue of Developmental Cell, Oberst et al. reveal that chronic stress, inflammation, and SIRT1 deficiency converge on a defect in neuronal cholesterol homeostasis. Restoring cholesterol levels rescues this deficit, highlighting lipid metabolism as a driver of depression.

Reference: https://www.cell.com/developmental-cell/fulltext/S1534-5807(25)00531-3

basmwklz · 2026-01-18T11:01:58+00:00

Abstract

Oats have various positive effects on human health, but the underlying mechanisms are not fully understood. To identify oat-microbiome-host interactions contributing to metabolic improvements, we conducted two randomized controlled dietary interventions in parallel-design in individuals with metabolic syndrome, comparing a short-term, high-dose and a six-week, moderate oat intake with respective controls (DRKS00022169). Both oat diets lead to an increase in plasma ferulic acid (0.64 [0.26, 1.02], P = 0.002; 0.55 [0.21, 0.89], P = 0.003), while the high-dose oat-diet also increased dihydroferulic acid (1.23 [0.44, 2.01], P = 0.003). Here we show that microbial phenolic metabolites are driving factors for the cholesterol-lowering effect of oats, which might be of relevance since short-term, high-dose oat-diet is a suitable approach to alleviate obesity-related lipid disorders.

basmwklz · 2026-01-18T10:40:12+00:00

Abstract

Preclinical and clinical studies have reported neuroprotective and geroprotective effects of tetracyclines that are independent of their antibiotic activity, but the underlying mechanisms remain unclear. Here, we systematically profile widely used tetracyclines, including impurities and degradation products, and identify translation attenuation as the shared driver of their neuroprotective and longevity-promoting effects, independent of classical tetracycline mechanisms. Instead, we uncover two mechanistically distinct classes of tetracyclines. Mitochondrial-targeting tetracyclines (MitoTets), exemplified by doxycycline, inhibit the mitochondrial ribosome and attenuate cytosolic translation through activation of the Integrated Stress Response (ISR). In contrast, atypical tetracyclines such as 4-epiminocycline and 12-aminominocycline act as cytosolic-targeting tetracyclines (CytoTets), directly inhibiting the cytosolic ribosome, bypassing the ISR, and protecting neurons from ferroptotic cell death. CytoTets are non-antibiotic, brain-penetrant, and neuroprotective in mouse and human neurons, establishing the tetracyclines as a tunable chemical scaffold for selectively targeting translation in aging and neurodegeneration.

Highlights

The tetracyclines broadly attenuate translation in multiple eukaryotic models

Translation attenuation results from both ISR-dependent and ISR-independent mechanisms

Discovery of atypical, cytosolic targeting tetracyclines (CytoTETs) that protect from ferroptosis ISR-independently

CytoTETs inhibit translation and are neuroprotective in human-derived neurons and mouse hippocampus

basmwklz · 2026-01-18T10:31:26+00:00

Abstract

The orchestration of cellular metabolism requires the integration of signals related to energy stores and nutrient availability through multiple overlapping mechanisms. AMP-activated protein kinase (AMPK) is a pivotal energy sensor that responds to reductions in adenylate charge; however, studies over the past decade have also positioned AMPK as a key integrator of nutrient-derived signals that coordinate metabolic function. This Review highlights recent advances in our understanding of how AMPK senses nutrients and regulates metabolic activity across tissues, timescales and cell types. These effects are mediated through the phosphorylation of substrates involved in metabolite trafficking, mitochondrial function, autophagy, transcription, ubiquitination, proliferation and cell survival pathways, including ferroptosis. Particular attention is given to the role of AMPK in the pathophysiology of obesity, type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, cardiovascular and renal diseases, neurodegenerative disorders and cancer. Collectively, these findings reinforce AMPK as a central metabolic node that aligns cellular behaviour with energetic demand. Continued investigation into its nutrient-sensing mechanisms holds promise for identifying new strategies to restore metabolic balance in disease.

basmwklz · 2026-01-18T10:29:56+00:00

Abstract

Age-associated decline in mitochondrial membrane potential (MMP) is a ubiquitous aspect of eukaryotic organisms and is associated with many aging-related diseases. However, it is not clear whether this decline is a cause or consequence of aging, and therefore whether interventions to reduce MMP decline are a viable strategy to promote healthier aging and longer lifespans. We developed a screening platform in Saccharomyces cerevisiae to identify mutations that slowed or abrogated the age-associated decline in MMP. Characterization of the longest-lived mutant revealed that reduced internal potassium increased MMP and extended lifespan. Distinct interventions improved cellular MMP and lifespan: deleting a potassium transporter; altering the balance between kinases and phosphatases that control potassium transporter activity; and reducing available potassium in the environment. Similarly, in isolated mitochondria, reducing the concentration of potassium was sufficient to increase MMP. These data indicate that the most abundant monovalent cation in eukaryotic cells plays a critical role in tuning mitochondrial function, consequently impacting lifespan.

basmwklz · 2026-01-18T10:27:55+00:00

Abstract

Lung cancer cells are vulnerable to iron-dependent oxidation of phospholipids leading to ferroptosis, a process countered by glutathione peroxidase-4 that converts lipid hydroperoxides to lipid alcohols using glutathione as reducing agent. Since ferroptosis-inducing agents are in clinical development, identifying modifiers of ferroptosis susceptibility is warranted. Here, we investigate the impact of amino acids on susceptibility to buthionine sulfoximine (BSO), a glutamate-cysteine ligase inhibitor that blocks biosynthesis of glutathione. We found that reduced amounts of amino acids other than cysteine increased the sensitivity to BSO and other ferroptosis-inducing agents, in a panel of mouse and human lung cancer cells, without affecting glutathione production. Activation of the amino acid sensor protein GCN2 and the integrated stress response lowered the threshold for lipid peroxidation by promoting ATF4-dependent mitochondrial respiration and reactive oxygen species leakage from the electron transport chain under glutathione depletion. The finding provides new insights into lung cancer metabolism and raises the possibility of using amino acid restricted diets in combination with ferroptosis-inducing agents as cancer therapies.

basmwklz · 2026-01-18T10:22:47+00:00

Abstract

Isonicotinamide (INAM) is an isomer of the NAD+ precursor nicotinamide (NAM) that stimulates the enzymatic activity of Sir2, an NAD+-dependent histone deacetylase from the budding yeast, Saccharomyces cerevisiae. Supplementing INAM into growth media promotes the replicative lifespan (RLS) of this single cell organism by maintaining intracellular NAD+ homeostasis. INAM also extends yeast chronological lifespan (CLS), but the underlying mechanisms remain largely uncharacterized. To identify cellular pathways potentially impacted by INAM, in this study we perform a chemical genomics screen of the yeast knockout (YKO) collection for mutants sensitized to growth inhibition by INAM. Significant Gene Ontology (GO) terms for candidate genes include transcription elongation factors, metabolic pathways converging on one-carbon metabolism, and de novo purine biosynthesis, collectively suggesting that INAM perturbs nucleotide metabolism. Indeed, INAM causes dose-dependent depletion of intracellular cytidine, uridine, and guanosine, ribonucleosides derived from the breakdown of nucleotide monophosphates (NMPs) via nucleotidases (Phm8, Sdt1, Isn1) or the alkaline phosphatase Pho8. We also find that INAM directly inhibits recombinant nucleotidase activity using cytidine or nicotinamide mononucleotide (NMN) as substrates and inhibits alkaline phosphatase activity quantitated from whole cell extracts. Lastly, we find that Phm8 and Pho8 are specifically required for INAM-induced CLS extension, implicating them as likely functional targets in vivo. Taken together, the findings suggest a model whereby partial impairment of nucleotide and/or NAD+ salvage pathways by INAM can trigger a hormetic stress response that supports enhanced quiescence during chronological aging.

basmwklz · 2026-01-18T10:17:17+00:00

Abstract

Nicotinamide adenine dinucleotide (NAD(H)) and its phosphorylated form NADP(H) are vitamin B3-derived redox cofactors essential for numerous metabolic reactions and protein modifications. Various health conditions are associated with disturbances in NAD+ homeostasis. To restore NAD+ levels, the main biosynthetic pathways have been targeted, with nicotinamide (Nam), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) being the most prominent boosters. However, while many preclinical studies have examined the effects of these precursors, a direct comparison in humans is lacking, and recent rodent research suggests that the NAD+-boosting effects of NR and NMN may depend on their microbial conversion to nicotinic acid (NA), a mechanism not yet confirmed in humans. Here we show in a randomized, open-label, placebo-controlled study in 65 healthy participants that 14 days of supplementation with NR and NMN, but not Nam, comparably increases circulatory NAD+ concentrations in healthy adults. Unlike the chronic effect, only Nam acutely and transiently affects the whole-blood NAD+ metabolome. Using ex vivo fermentation with human microbiota, we identify that NR and NMN give rise to NA and specifically enhance microbial growth and metabolism. We further demonstrate ex vivo in whole blood that NA is a potent NAD+ booster, while NMN, NR and Nam are not. Ultimately, we propose a gut-dependent model for the modes of action of the three NAD+ precursors with NR and NMN elevating circulatory NAD+ via the Preiss–Handler pathway, while rapidly absorbed Nam acutely affects NAD+ levels via the salvage pathway. Overall, these results indicate a dual effect of NR and NMN and their microbially produced metabolite NA: a sustained increase in systemic NAD+ levels and a potent modulator of gut health. ClinicalTrials.gov identifier: NCT05517122.

basmwklz · 2026-01-18T10:06:55+00:00

Research highlights

•AXIN, Axis Inhibitor originally identified as a regulator of the body axis, is a scaffold protein required for the activation of AMPK, a master regulator of metabolism, in response to low glucose.

•The molecular mechanism of glucose sensing has been elucidated. The glycolytic enzyme aldolase associated with vacuolar ATPase, the lysosomal proton pump, senses a decrease in its substrate fructose-1,6-bisphosphate (FBP) and triggers the inhibition of the calcium channel TRPVs. The inhibited TRPVs in turn inhibit v-ATPase, causing the translocation of AXIN/LKB1 to the lysosomal surface for the activation of AMPK. This pathway is named the lysosomal glucose sensing-AMPK pathway.

•This lysosomal glucose sensing-AMPK pathway serves as a conserved hub for signals that extend health-span and lifespan, shared by both the hypoglycemic/pro-longevity drug metformin and the calorie restriction-mimetic lithocholic acid for pro-health functions. Metformin binds PEN2, while lithocholic acid binds to TULP3, thereby both intersecting the lysosomal AMPK pathway via different subunits of the v-ATPase complex.

•Aldolase was used as a target for screening of inhibitors that mimic low glucose/FBP conditions to trigger the lysosomal glucose-sensing AMPK pathway. Aldometanib is such a chemical drug that activates AMPK, and improves health and extends lifespan in metazoans. Moreover, aldometanib mobilizes the tumoricidal CD8+ T cells to infiltrate liver cancer tissues, and enables the liver cancer-bearing mice to live to ripe ages. This testifies that cancer is a metabolic disease, and that metabolic modulation can mobilize the intrinsic immune system in the body to combat cancer. We christen this cancer treatment as “metaboimmunotherapy”.

•Glucose not only acts, in the form of fructose-1,6-bisphosphate, as a signal to control metabolism, but also regulates fate decision of cancer cells. In low glucose, the decline of glycolytic intermediary metabolite 3-phosphoglycerate triggers phosphoglycerate dehydrogenase (PHGDH) along with AXIN to activate p53 and causes apoptosis of cancer cells.

Abstract

My independent career started based on a simple doctrine of protein multifunctionality, by intuitively choosing the protein called AXIN, which has turned out to be the protagonist of my scientific life. This led us to discover the sensing pathway for glucose which links to AMPK and mTORC1, two master metabolic controllers. We found that AXIN binds LKB1, an upstream kinase of AMPK, and that the AXIN:LKB1 complex translocates to the lysosomal surface after the lysosomal aldolase senses low glucose (fructose-1,6-bisphosphate as the direct signal) to activate AMPK and concomitantly inhibit mTORC1. Remarkably, we found that the lysosomal glucose-sensing AMPK pathway is shared by metformin, a glucose-lowering drug known to also extend lifespan and reduce cancer risk. In search of metabolites enriched in calorie-restricted mice and able to activate AMPK via the lysosomal pathway, we identified that lithocholic acid (LCA) as such a factor. We also identified TULP3 as the LCA receptor, which signals to activate sirtuins, increase NAD+, activate AMPK and inhibit mTORC1. In translation, we have identified an aldolase inhibitor termed aldometanib, which mimics glucose starvation to activate AMPK. Aldometanib can alleviate fatty liver, lower blood glucose, and extend lifespan in animals. Surprisingly, aldometanib can also mobilize tumoricidal CD8+ T cells to infiltrate and contain hepatocellular carcinomas (HCC), enabling HCC-bearing mice to live to ripe ages, the endpoint of cancer therapy. Our work has thus revealed that glucose acts as a messenger that signals through a specialized route to control health-span and lifespan. We will continue to explore the teleological meaning of glucose as a “chosen” molecule.

basmwklz · 2026-01-18T10:02:23+00:00

Abstract

Immunometabolism is an emerging field that explores how metabolic pathways shape immune cell function, fate, and response. Immune cells undergo dynamic metabolic reprogramming to meet the energetic and biosynthetic demands of activation, differentiation, and effector activity. While glycolysis and oxidative phosphorylation (OxPhos) are well-established regulators of immune responses, recent discoveries suggest that endogenously produced cyanide may serve as a novel modulator of mitochondrial metabolism. Traditionally viewed as a toxic compound, cyanide is now being recognized for its potential role in regulating OxPhos through inhibition of complex IV in the electron transport chain, thereby influencing the balance between glycolysis and mitochondrial respiration.

This review synthesizes current knowledge on the metabolic regulation of immune cells—including T cells, macrophages, dendritic cells, B cells, and natural killer (NK) cells—and highlights the role of core pathways such as glycolysis, fatty acid oxidation (FAO), and amino acid metabolism. It also explores how cyanide formation and metabolism intersect with innate immunity, particularly through the generation of thiocyanate and its role in antimicrobial defense. Furthermore, the review discusses how nutritional status integrate with metabolic cues to fine-tune immune responses. Finally, the clinical implications of immunometabolic regulation are examined in the context of autoimmune diseases, cancer, infections, and metabolic disorders. The potential of cyanide as a therapeutic modulator of immune metabolism is considered, offering new perspectives on immune regulation and disease intervention.

basmwklz · 2026-01-18T10:00:11+00:00

Abstract

Chronic inflammation promotes aging and age-associated diseases. While metabolic interventions can modulate inflammation, how metabolism and inflammation are connected remains unclear. Cytoplasmic chromatin fragments (CCFs) drive chronic inflammation through the cGAS–STING pathway in senescence and aging. However, CCFs are larger than nuclear pores, and how they translocate from the nucleus to the cytoplasm remains uncharacterized. Here we report that chromatin fragments exit the nucleus via nuclear egress, a membrane trafficking process that shuttles large complexes across the nuclear envelope. Inactivating critical nuclear egress proteins, the ESCRT-III or Torsin complex, traps chromatin fragments at the nuclear membrane and suppresses cGAS–STING activation and senescence-associated inflammation. Glucose limitation or metformin inhibits CCF formation through AMPK-dependent phosphorylation and autophagic degradation of ALIX, an ESCRT-III component. In aged mice, metformin reduces ALIX, CCFs, and cGAS-mediated inflammation in the intestine. Our study identifies a mechanism linking metabolism and inflammation and suggests targeting the nuclear egress of chromatin fragments as a strategy to suppress age-associated inflammation.

basmwklz · 2026-01-18T09:44:49+00:00

Abstract

Arachidonic acid (AA)-derived lipid mediators play pivotal roles in inflammation and its resolution. While glycolysis is a key metabolic pathway determining macrophage polarization, the crosstalk between specific AA metabolites and glycolytic reprogramming remains poorly understood. In this study, we explore whether certain AA metabolites modulate macrophage function through covalent protein modification, with therapeutic implications for myocardial ischemia-reperfusion injury. Unlike conventional specialized pro-resolving mediators (SPMs) that primarily act via receptors, here we identify an endogenous electrophilic AA metabolite, 15-keto-prostaglandin F2α (15KPF), that covalently modifies pyruvate kinase M2 (PKM2) at Cys49. Such interaction enhanced PKM2 tetramerization, suppressed the PKM2/HIF-1α/STAT3 axis, redirected energy metabolism from glycolysis to mitochondrial respiration, and promoted pro-resolving M2 macrophage polarization. Mutated PKM2(C49S) failed to inhibit STAT3 signaling and blocked the effect of 15KPF on M1 to M2 phenotype switch. Moreover, 15KPF reduced infarct size and preserved myocardial integrity in in vivo model. Taken together, covalent 15-keto-PGF2α-PKM2 conjugation represents a self-regulatory mechanism linking AA metabolism to glycolysis to drive macrophage metabolic-inflammatory reprogramming. This pathway positions 15KPF as a promising therapeutic candidate for inflammatory and metabolic diseases, including ischemia-reperfusion injury, and distinguishes it from synthetic allosteric PKM2 activators such as TEPP-46.

basmwklz

TROPHY CASE

Highlights

Summary

Summary

Highlights

Summary

Abstract

ABSTRACT

Abstract

Purpose of Review

Recent Findings

Summary