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Background: Geroscience focuses on interventions to mitigate molecular changes associated with aging. Lifestyle modifications, medications, and social factors influence the aging process, yet the complex molecular mechanisms require an in-depth exploration of the epigenetic landscape. The specific epigenetic clock and predictor effects of a vegan diet, compared to an omnivorous diet, remain underexplored despite potential impacts on aging-related outcomes., Methods: This study examined the impact of an entirely plant-based or healthy omnivorous diet over 8 weeks on blood DNA methylation in paired twins. Various measures of epigenetic age acceleration (PC GrimAge, PC PhenoAge, DunedinPACE) were assessed, along with system-specific effects (Inflammation, Heart, Hormone, Liver, and Metabolic). Methylation surrogates of clinical, metabolite, and protein markers were analyzed to observe diet-specific shifts., Results: Distinct responses were observed, with the vegan cohort exhibiting significant decreases in overall epigenetic age acceleration, aligning with anti-aging effects of plant-based diets. Diet-specific shifts were noted in the analysis of methylation surrogates, demonstrating the influence of diet on complex trait prediction through DNA methylation markers. An epigenome-wide analysis revealed differentially methylated loci specific to each diet, providing insights into the affected pathways., Conclusions: This study suggests that a short-term vegan diet is associated with epigenetic age benefits and reduced calorie intake. The use of epigenetic biomarker proxies (EBPs) highlights their potential for assessing dietary impacts and facilitating personalized nutrition strategies for healthy aging. Future research should explore the long-term effects of vegan diets on epigenetic health and overall well-being, considering the importance of proper nutrient supplementation., Trial Registration: Clinicaltrials.gov identifier: NCT05297825., (© 2024. The Author(s).)

Background: The DIETFITS trial reported no significant difference in 12-month weight loss between a healthy low-fat and healthy low-carbohydrate diet. Participants were instructed to restrict fat or carbohydrates to levels consistent with a ketogenic or ultra low-fat diet for 2  months and to subsequently increase intakes until they achieved a comfortable maintenance level., Objective: To compare 3- and 12-month changes in body weight and cardiometabolic risk factors between a subsample of participants who reported 3-month fat or carbohydrates intakes consistent with either a ketogenic-like diet (KLD) or ultra low-fat diet (ULF)., Design: 3-month and 12-month weight and risk factor outcomes were compared between KLD ( n  = 18) and ULF ( n  = 21) sub-groups of DIETFITS participants (selected from n  = 609, healthy overweight/obese, aged 18-50  years)., Results: Less than 10% of DIETFITS participants met KLD or ULF criteria at 3-months. Both groups achieved similar weight loss and insulin resistance improvements at 3-months and maintained them at 12- months. Significant differences at 3-months included a transient ~12% increase in LDL cholesterol (LDL-C) for KLD with a concomitant greater reduction in log(TG/HDL), a measure of LDL-C's atherogenic potential. The latter was maintained at 12-months, despite substantial diet recidivism for both groups, whereas LDL-C levels were similar for ULF at baseline and 12-months. KLD participants achieved and maintained the greatest reductions in added sugars and refined grains at 3- months and 12-months, whereas ULF participants reported a 50% increase in refined grains intake from baseline to 12-months., Conclusion: Among the ~10% of study participants that achieved the most extreme restriction of dietary fat vs. carbohydrate after 3  months, weight loss and improvement in insulin sensitivity were substantial and similar between groups. At 12  months, after considerable dietary recidivism, the few significant differences in diet quality and blood lipid parameters tended to favor KLD over ULF., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Aronica, Landry, Rigdon and Gardner.)

Background: The Diet Intervention Examining The Factors Interacting with Treatment Success (DIETFITS) trial demonstrated that meaningful weight loss can be achieved with either a "healthy low-carbohydrate diet" (LCD) or "healthy low-fat diet" (LFD). However, because both diets substantially decreased glycemic load (GL), the dietary factors mediating weight loss remain unclear., Objectives: We aimed to explore the contribution of macronutrients and GL to weight loss in DIETFITS and examine a hypothesized relationship between GL and insulin secretion., Design: This study is a secondary data analysis of the DIETFITS trial, in which participants with overweight or obesity (aged 18-50 y) were randomized to a 12-mo LCD (N = 304) or LFD (N = 305)., Results: Measures related to carbohydrate intake (total amount, glycemic index, added sugar, and fiber) showed strong associations with weight loss at 3-, 6-, and 12-mo time points in the full cohort, whereas those related to total fat intake showed weak to no associations. A biomarker of carbohydrate (triglyceride/HDL cholesterol ratio) predicted weight loss at all time points (3-mo: β [kg/biomarker z-score change] = 1.1, P = 3.5 × 10 -9 ; 6-mo: β = 1.7, P = 1.1 × 10 -9 ; and 12-mo: β = 2.6, P = 1.5 × 10 -15 ), whereas that of fat (low-density lipoprotein cholesterol + HDL cholesterol) did not (all time points: P = NS). In a mediation model, GL explained most of the observed effect of total calorie intake on weight change. Dividing the cohort into quintiles of baseline insulin secretion and GL reduction revealed evidence of effect modification for weight loss, with P = 0.0009 at 3 mo, P = 0.01 at 6 mo, and P = 0.07 at 12 mo., Conclusions: As predicted by the carbohydrate-insulin model of obesity, weight loss in both diet groups of DIETFITS seems to have been driven by the reduction of GL more so than dietary fat or calories, an effect that may be most pronounced among those with high insulin secretion. These findings should be interpreted cautiously in view of the exploratory nature of this study., Trial Registration: ClinicalTrials.gov (NCT01826591)., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Consensus has not been reached on what constitutes an optimal diet in individuals with prediabetes and type 2 diabetes mellitus (T2DM), especially between low-carbohydrate options., Objectives: We compared 2 low-carbohydrate diets with 3 key similarities (incorporating nonstarchy vegetables and avoiding added sugars and refined grains) and 3 key differences (incorporating compared with avoiding legumes, fruits, and whole, intact grains) for their effects on glucose control and cardiometabolic risk factors in individuals with prediabetes and T2DM., Methods: Keto-Med was a randomized, crossover, interventional trial. Forty participants aged ≥18 years with prediabetes or T2DM followed the well-formulated ketogenic diet (WFKD) and the Mediterranean-plus diet (Med-Plus) for 12 weeks each, in random order. The diets shared the 3 key similarities noted above. The Med-Plus incorporated legumes, fruits, and whole, intact grains, while the WFKD avoided them. The primary outcome was the percentage change in glycated hemoglobin (HbA1c) after 12 weeks on each diet. Secondary and exploratory outcomes included percentage changes in body weight, fasting insulin, glucose, and blood lipids; average glucose from continuous glucose monitor (CGM), and nutrient intake., Results: The primary analysis was of 33 participants with complete data. The HbA1c values did not differ between diets at 12 weeks. Triglycerides decreased more for the WFKD [percentage changes, -16% (SEM, 4%) compared with -5% (SEM, 6%) for the Med-Plus; P = 0.02] and LDL cholesterol was higher for the WFKD [percentage changes, +10% (SEM, 4%) compared with -5% (SEM, 5%) for the Med-Plus; P = 0.01]. Weight decreased 8% (SEM, 1%) compared with 7% (SEM, 1%) and HDL cholesterol increased 11% (SEM, 2%) compared with 7% (SEM, 3%) for the WFKD compared with the Med-Plus, respectively; however, there was a significant interaction of diet × order for both. Participants had lower intakes of fiber and 3 nutrients on the WFKD compared with the Med-Plus. Twelve-week follow-up data suggest the Med-Plus is more sustainable., Conclusions: HbA1c values were not different between diet phases after 12 weeks, but improved from baseline on both diets, likely due to several shared dietary aspects. The WFKD led to a greater decrease in triglycerides, but also had potential untoward risks from elevated LDL cholesterol and lower nutrient intakes from avoiding legumes, fruits, and whole, intact grains, as well as being less sustainable. This trial was registered at clinicaltrials.gov as NCT03810378., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Metabolic detoxification (detox)-or biotransformation-is a physiological function that removes toxic substances from our body. Genetic variability and dietary factors may affect the function of detox enzymes, thus impacting the body's sensitivity to toxic substances of endogenous and exogenous origin. From a genetic perspective, most of the current knowledge relies on observational studies in humans or experimental models in vivo and in vitro, with very limited proof of causality and clinical value. This review provides health practitioners with a list of single nucleotide polymorphisms (SNPs) located within genes involved in Phase I and Phase II detoxification reactions, for which evidence of clinical utility does exist. We have selected these SNPs based on their association with interindividual variability of detox metabolism in response to certain nutrients in the context of human clinical trials. In order to facilitate clinical interpretation and usage of these SNPs, we provide, for each of them, a strength of evidence score based on recent guidelines for genotype-based dietary advice. We also present the association of these SNPs with functional biomarkers of detox metabolism in a pragmatic clinical trial, the LIFEHOUSE study.

The working definition of health is often the simple absence of diagnosed disease. This common standard is limiting given that changes in functional health status represent early warning signs of impending health declines. Longitudinal assessment of functional health status may foster prevention of disease occurrence and modify disease progression. The LIFEHOUSE (Lifestyle Intervention and Functional Evaluation-Health Outcomes SurvEy) longitudinal research project explores the impact of personalized lifestyle medicine approaches on functional health determinants. Utilizing an adaptive tent-umbrella-bucket design, the LIFEHOUSE study follows the functional health outcomes of adult participants recruited from a self-insured employee population. Participants were each allocated to the tent of an all-inclusive N-of-one case series. After assessing medical history, nutritional physical exam, baseline functional status (utilizing validated tools to measure metabolic, physical, cognitive, emotional and behavioral functional capacity), serum biomarkers, and genomic and microbiome markers, participants were assigned to applicable umbrellas and buckets. Personalized health programs were developed and implemented using systems biology formalism and functional medicine clinical approaches. The comprehensive database (currently 369 analyzable participants) will yield novel interdisciplinary big-health data and facilitate topological analyses focusing on the interactome among each participant's genomics, microbiome, diet, lifestyle and environment.

Pre-mRNA splicing is a key process in the regulation of gene expression. In the fission yeast Schizosaccharomyces pombe , Nrl1 regulates splicing and expression of several genes and non-coding RNAs, and also suppresses the accumulation of R-loops. Here, we report analysis of interactions between Nrl1 and selected RNA-processing proteins and regulation of Nrl1 function by phosphorylation. Bacterial two-hybrid system (BACTH) assays revealed that the N-terminal region of Nrl1 is important for the interaction with ATP-dependent RNA helicase Mtl1 while the C-terminal region of Nrl1 is important for interactions with spliceosome components Ctr1, Ntr2, and Syf3. Consistent with this result, tandem affinity purification showed that Mtl1, but not Ctr1, Ntr2, or Syf3, co-purifies with the N-terminal region of Nrl1. Interestingly, mass-spectrometry analysis revealed that in addition to previously identified phosphorylation sites, Nrl1 is also phosphorylated on serines 86 and 112, and that Nrl1-TAP co-purifies with Cka1, the catalytic subunit of casein kinase 2. In vitro assay showed that Cka1 can phosphorylate bacterially expressed Nrl1 fragments. An analysis of non-phosphorylatable nrl1 mutants revealed defects in gene expression and splicing consistent with the notion that phosphorylation is an important regulator of Nrl1 function. Taken together, our results provide insights into two mechanisms that are involved in the regulation of the spliceosome-associated factor Nrl1, namely domain-specific interactions between Nrl1 and RNA-processing proteins and post-translational modification of Nrl1 by phosphorylation.

In 2015, the Dietary Guidelines for Americans (DGA) eliminated the historical upper limit of 300 mg of dietary cholesterol/day and shifted to a more general recommendation that cholesterol intake should be limited. The primary aim of this secondary analysis of the Diet Intervention Examining the Factors Interacting With Treatment Success (DIETFITS) weight loss diet trial was to evaluate the associations between 12-month changes in dietary cholesterol intake (mg/day) and changes in plasma lipids, particularly low-density lipoprotein (LDL) cholesterol for those following a healthy low-carbohydrate (HLC) diet. Secondary aims included examining high-density lipoprotein (HDL) cholesterol and triglycerides and changes in refined grains and added sugars. The DIETFITS trial randomized 609 healthy adults aged 18-50 years with body mass indices of 28-40 kg/m 2 to an HLC or healthy low-fat (HLF) diet for 12 months. Linear regressions examined the association between 12-month change in dietary cholesterol intake and plasma lipids in 208 HLC participants with complete diet and lipid data, adjusting for potential confounding variables. Baseline dietary cholesterol intake was 322 ± 173 (mean ± SD). At 12 months, participants consumed an average of 460 ± 227 mg/day of dietary cholesterol; 76% consumed over the previously recommended limit of 300 mg/day. Twelve-month changes in cholesterol intake were not significantly associated with 12-month changes in LDL-C, HDL-C, or triglycerides. Diet recall data suggested participants' increase in dietary cholesterol was partly due to replacing refined grains and sugars with eggs. An increase in daily dietary cholesterol intake to levels substantially above the previous 300 mg upper limit was not associated with a negative impact on lipid profiles in the setting of a healthy, low-carbohydrate weight loss diet.

Adherence is a critical factor to consider when interpreting study results from randomized clinical trials (RCTs) comparing one diet to another, but it is frequently not reported by researchers. The purpose of this secondary analysis of the Keto-Med randomized trial was to provide a detailed examination and comparison of the adherence to the two study diets (Well Formulated Ketogenic Diet (WFKD) and Mediterranean Plus (Med-Plus)) under the two conditions: all food being provided (delivered) and all food being obtained by individual participants (self-provided). Diet was assessed at six time points including baseline (×1), week 4 of each phase when participants were receiving food deliveries (×2), week 12 of each phase when participants were preparing and providing food on their own (×2), and 12 weeks after participants completed both diet phases and were free to choose their own diet pattern (×1). The adherence scores for WFKD and Med-Plus were developed specifically for this study. Average adherence to the two diet patterns was very similar during both on-study time points of the intervention. Throughout the study, a wide range of adherence was observed among participants-for both diet types and during both the delivery phase and self-provided phase. Insight from this assessment of adherence may aid other researchers when answering the important question of how to improve behavioral adherence during dietary trials. This study is registered at clinicaltrials.gov NCT03810378.

Background/objectives: Biological sex factors and sociocultural gender norms affect the physiology and behavior of weight loss. However, most diet intervention studies do not report outcomes by sex, thereby impeding reproducibility. The objectives of this study were to compare 12-month changes in body weight and composition in groups defined by diet and sex, and adherence to a healthy low carbohydrate (HLC) vs. healthy low fat (HLF) diet., Participants/methods: This was a secondary analysis of the DIETFITS trial, in which 609 overweight/obese nondiabetic participants (age, 18-50 years) were randomized to a 12-month HLC (n = 304) or HLF (n = 305) diet. Our first aim concerned comparisons in 12-month changes in weight, fat mass, and lean mass by group with appropriate adjustment for potential confounders. The second aim was to assess whether or not adherence differed by diet-sex group (HLC women n = 179, HLC men n = 125, HLF women n = 167, HLF men n = 138)., Results: 12-month changes in weight (p < 0.001) were different by group. HLC produced significantly greater weight loss, as well as greater loss of both fat mass and lean mass, than HLF among men [-2.98 kg (-4.47, -1.50); P < 0.001], but not among women. Men were more adherent to HLC than women (p = 0.02). Weight loss estimates within group remained similar after adjusting for adherence, suggesting adherence was not a mediator., Conclusions: By reporting outcomes by sex significant weight loss differences were identified between HLC and HLF, which were not recognized in the original primary analysis. These findings highlight the need to consider sex in the design, analysis, and reporting of diet trials.

The ketogenic diet (KD) is a low-carbohydrate, high-fat, adequate-protein diet proven to be effective for the reversal of obesity, metabolic syndrome and type 2 diabetes, and holding therapeutic potential for the prevention and treatment of other chronic diseases. Genetic and dynamic markers of KD response may help to identify individuals most likely to benefit from KD and point to individuals at higher risk for adverse health outcomes. Here, we provide a clinician-friendly review of state-of-the-art research on biomarkers of KD response for a variety of outcomes including weight loss, body composition and cognitive performance drawing data from both intervention trials and case reports of rare inborn errors of metabolism. We also present a selection of the most promising candidate genes to evaluate in future studies and discuss key aspects of study design and variant interpretation that may help accelerate the implementation of these biomarkers in clinical practice., Competing Interests: Competing interests: JV is a founder and equity holder in Virta Health, scientific advisors for Atkins Nutritionals and UCAN, and receives royalties from books on ketogenic diets. AP is coowner of the company Poff Medical Consulting and Communications which provides scientific consulting services. AP is also coowner of the company Metabolic Health Initiative, LLC which hosts the annual scientific conference Metabolic Health Summit. AP is an inventor on patents related to ketone technology. DPD is an inventor on International Patent # PCT/US2014/031237 University of South Florida: Compositions and Methods for Producing Elevated and Sustained Ketosis. DPD is a coowner of the company Ketone Technologies, a company specialised in scientific consulting., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The goal of the 2018 American Society for Parenteral and Enteral Nutrition (ASPEN) Research Workshop was to explore the influence of nutrition and dietary exposure to xenobiotics on the epigenome during critical periods in development and how these exposures influence both disease incidence and severity transgenerationally. A growing compendium of research indicates that the incidence and severity of common and costly human diseases may be influenced by dietary exposures and deficiencies that modify the epigenome. The greatest periods of vulnerability to these exposures are the periconception period and early childhood. Xenobiotics in the food chain, protein malnutrition, and methyl donor deficiencies could have a profound bearing on the risk of developing heart disease, diabetes, obesity, hypertension, and mental illness over multiple generations. The financial impact and the life burden of these diseases are enormous. These and other aspects of nutrition, epigenetics, and health are explored in this research workshop., (© 2019 American Society for Parenteral and Enteral Nutrition.)

Background: For low-carbohydrate diets, a public health approach has focused on the replacement of carbohydrates with unsaturated fats. However, little research exists on the impacts of saturated fat intake on the lipid profile in the context of whole-food-based low-carbohydrate weight-loss diets., Objectives: The primary aim of this secondary analysis of the DIETFITS weight loss trial was to evaluate the associations between changes in percentage of dietary saturated fatty acid intake (%SFA) and changes in low-density lipoproteins, high-density lipoproteins, and triglyceride concentrations for those following a healthy low-carbohydrate (HLC) diet. The secondary aim was to examine these associations specifically for HLC dieters who had the highest 12-month increases in %SFA., Methods: In the DIETFITS trial, 609 generally healthy adults, aged 18-50 years, with body mass indices of 28-40 kg/m2 were randomly assigned to a healthy low-fat (HLF) or HLC diet for 12 months. In this analysis, linear regression, both without and with adjustment for potential confounders, was used to measure the association between 12-month change in %SFA and blood lipids in 208 HLC participants with complete diet and blood lipid data., Results: Participants consumed an average of 12-18% of calories from SFA. An increase of %SFA, without significant changes in absolute saturated fat intake, over 12 months was associated with a statistically significant decrease in triglycerides in the context of a weight-loss study in which participants simultaneously decreased carbohydrate intake. The association between increase in %SFA and decrease in triglycerides was no longer significant when adjusting for 12-month change in carbohydrate intake, suggesting carbohydrate intake may be a mediator of this relationship., Conclusions: Those on a low-carbohydrate weight-loss diet who increase their percentage intake of dietary saturated fat may improve their overall lipid profile provided they focus on a high-quality diet and lower their intakes of both calories and refined carbohydrates. This trial was registered at clinicaltrials.gov as NCT01826591.

Aim: Obesity results from the interaction of genetic and environmental factors, which may involve epigenetic mechanisms such as DNA methylation (DNAm)., Materials & Methods: We have followed the PRISMA protocol to select studies that analyzed DNAm at baseline and end point of a weight loss intervention using either candidate-locus or genome-wide approaches., Results: Six genes displayed weight loss associated DNAm across four out of nine genome-wide studies. Weight loss is associated with significant but small changes in DNAm across the genome, and weight loss outcome is associated with individual differences in baseline DNAm at several genomic locations., Conclusion: The identified weight loss associated DNAm markers, especially those showing reproducibility across different studies, warrant validation by further studies with robust design and adequate power.

The formation of RNA-DNA hybrids, referred to as R-loops, can promote genome instability and cancer development. Yet the mechanisms by which R-loops compromise genome instability are poorly understood. Here, we establish roles for the evolutionarily conserved Nrl1 protein in pre-mRNA splicing regulation, R-loop suppression and in maintaining genome stability. nrl1Δ mutants exhibit endogenous DNA damage, are sensitive to exogenous DNA damage, and have defects in homologous recombination (HR) repair. Concomitantly, nrl1Δ cells display significant changes in gene expression, similar to those induced by DNA damage in wild-type cells. Further, we find that nrl1Δ cells accumulate high levels of R-loops, which co-localize with HR repair factors and require Rad51 and Rad52 for their formation. Together, our findings support a model in which R-loop accumulation and subsequent DNA damage sequesters HR factors, thereby compromising HR repair at endogenously or exogenously induced DNA damage sites, leading to genome instability., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The loading of small interfering RNAs (siRNAs) and microRNAs into Argonaute proteins is enhanced by Hsp90 and ATP in diverse eukaryotes. However, whether this loading also occurs independently of Hsp90 and ATP remains unclear. We show that the Tetrahymena Hsp90 co-chaperone Coi12p promotes siRNA loading into the Argonaute protein Twi1p in both ATP-dependent and ATP-independent manners in vitro. The ATP-dependent activity requires Hsp90 and the tetratricopeptide repeat (TPR) domain of Coi12p, whereas these factors are dispensable for the ATP-independent activity. Both activities facilitate siRNA loading by counteracting the Twi1p-binding protein Giw1p, which is important to specifically sort the 26- to 32-nt siRNAs to Twi1p. Although Coi12p lacking its TPR domain does not bind to Hsp90, it can partially restore the siRNA loading and DNA elimination defects of COI12 knockout cells, suggesting that Hsp90- and ATP-independent loading of siRNA occurs in vivo and plays a physiological role in Tetrahymena., (© 2015 The Authors. Published under the terms of the CC BY 4.0 license.)