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In this extensive prospective cohort investigation, which involved over 50,000 participants, we identified 15 plasma metabolites related to lifestyle factors, predominantly consisting of lipids. Via enrichment analysis, we propose that lifestyle factors may modulate the linoleic acid metabolism pathway and the glycerolipid metabolism pathway, thus affecting overall health. Following this, we utilized accelerated failure time models to assess the influence of various factors, including metabolites, on the latent period of chronic kidney disease (CKD). Our results offer new perspectives on the possibility of early intervention and prevention of kidney disease, even though additional experimental and clinical studies are necessary to substantiate these findings.
In our investigation, 15 plasma metabolites were linked to a holistic lifestyle, incorporating various fatty acids, lipoprotein subclasses, and derived markers, including saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, linoleic acid, triglycerides, HDL, LDL, and VLDL, among others. Additionally, prior studies have indicated that plasma metabolites associated with differing lifestyle combinations play a vital role in clarifying the metabolic mechanisms through which lifestyle impacts health. For example, a multi-cohort research effort identified the metabolomic profiles of the Alternative Healthy Eating Index (AHEI), demonstrating strong and positive correlations between AHEI scores and fatty acid unsaturation, as well as the proportion and concentration of polyunsaturated fatty acids, encompassing omega-3 fatty acids (notably docosahexaenoic acid) and omega-6 fatty acids (especially linoleic acid). In contrast, AHEI scores showed negative correlations with the concentrations of saturated fatty acids and monounsaturated fatty acids30. Another EPIC cohort study revealed that obesity can cause modifications in metabolic profiles marked by shifts in urinary amino acids, sphingomyelins, glutamate, and various phosphatidylcholines31. Furthermore, other lifestyle factors such as smoking32, sleep33, alcohol consumption34, and physical activity35were associated with changes in amino acids, fatty acids, lipoproteins, and fluid balance metabolites, indicating the intrinsic metabolic effects of lifestyle behaviors on health status from a metabolomics perspective. Moreover, based on our research outcomes, we speculate that lifestyle may mainly influence health by modulating lipid metabolism within the body. Anne-Julie Tessier and colleagues showed through four substantial cohort studies that lifestyle metabolomic profiling reflected lipid metabolic pathways, enhancing predictive capacities for overall mortality, cause-specific mortality, and longevity36. In a cohort investigation, researchers found associations between lifestyle factors and 81 plasma metabolites across various categories: lipids, lipoprotein subclasses, amino acids, fatty acids, ketone bodies, metabolites related to fluid balance, glycolysis-related metabolites, and inflammation-related metabolites37. The metabolites most strongly correlated with lifestyle included concentrations of HDL particles, total choline, citrate, linoleic acid, omega-3 fatty acids, and phosphatidylcholine. A separate cohort study conducted in Spain uncovered that an integrated lifestyle based on diet, physical activity, smoking status, alcohol usage, and BMI resulted in alterations in creatinine, acetone, citrate, and some lipid metabolites38. In addition, another UK Biobank study revealed associations between lifestyle and numerous lipid metabolites in plasma, including docosahexaenoic acid, omega-3 fatty acids to total fatty acids ratio, monounsaturated fatty acids to total fatty acids ratio, and linoleic acid to total fatty acids ratio, corroborating the results of our current study19. Nonetheless, due to the inconsistent definitions of lifestyle combinations and the varying metabolites measured in different studies, there may exist heterogeneity in metabolic profiles. More comprehensive studies, including standardized lifestyle definitions, plasma metabolite evaluations and longitudinal follow-up studies, are necessary to establish a solid scientific basis for developing more effective health strategies. Additionally, since the lifestyle-related metabolites we identified are largely derived data rather than direct metabolite concentrations, we chose key metabolites connected to lifestyle for enrichment analysis, instead of employing derived indices. For example, we selected linoleic acid rather than the “Linoleic Acid to Total Fatty Acids percentage” for enrichment analysis. Moreover, some metabolites are only categorized broadly (e.g., polyunsaturated fatty acids, monounsaturated fatty acids, saturated fatty acids) without specific KEGG IDs, which hampers the precise identification of metabolic pathways. Therefore, upcoming studies will need to achieve more accurate metabolite assessments and further validation of metabolic pathways.
In this research, we employed accelerated failure time models to investigate the elements affecting the onset of CKD. Among traditional risk determinants, smoking, hypertension, diabetes, and high BMI remain significant predictors for the development of CKD. These findings underscore the necessity of preventing CKD by prolonging the span of effective survival without the disease, highlighting the importance of proper management of chronic conditions and sustaining healthy lifestyle habits. Additionally, leveraging NMR-based metabolomics, we carried out a further analysis of plasma metabolites and discerned an association between triglycerides in large LDL particles and the onset of CKD. This emphasizes the crucial role of a low-fat diet and the regulation of lipid levels in promoting kidney health. Triglycerides in large LDL particles are linked to accelerated CKD progression. The mechanisms through which triglycerides in low-density lipoprotein (LDL) contribute to kidney damage have emerged as a significant research focus in chronic kidney disease (CKD). Studies have indicated that triglyceride-rich lipoproteins (TRLs) are elevated in CKD patients and may hasten kidney injury through multiple pathways. Firstly, high triglyceride levels are often accompanied by disturbances in lipid metabolism, leading to lipid accumulation in kidney tissues, particularly in the renal tubules and interstitial spaces. These deposits can provoke localized oxidative stress, increasing the production of reactive oxygen species (ROS), which subsequently causes cellular damage and apoptosis39. Furthermore, elevated triglycerides may modify the composition and function of lipoproteins, making them more prone to induce immune and inflammatory responses, thereby worsening local inflammation in the kidneys. The release of inflammatory cytokines such as TNF-α and IL-6 activates immune cells, further harming renal tubular epithelial cells and facilitating the deterioration of kidney function.[45] Additionally, the rise in triglycerides may influence fatty acid metabolism, causing elevated levels of free fatty acids within the kidneys. These free fatty acids can promote the fibrotic process in kidney tissues through various mechanisms, ultimately resulting in the further decline of renal function. Specifically, triglycerides, by altering lipid and fatty acid metabolism, activate signaling pathways.
related to fibrosis, oxidative stress, and inflammation, which lead to structural and functional impairment in the kidneys40. Consequently, in the management of kidney health, implementing a holistic lifestyle intervention is vital. In addition to advising a minimum of 150 minutes of moderate-intensity aerobic activity each week, sustaining a healthy BMI, ensuring 7–9 hours of quality sleep, restricting alcohol consumption, and promoting quitting smoking, dietary choices and blood lipid regulation are fundamental in safeguarding kidney function. A low-fat diet should emphasize sources of unsaturated fatty acids, such as oily fish, fish oil, and plant-derived oils. These food items not only deliver beneficial fats but are also abundant in omega-3 fatty acids, which have been demonstrated to aid in diminishing inflammation, enhancing cardiovascular health, and supporting kidney performance. Conversely, consumption of animal fats should be reduced, particularly from red meat, full-fat dairy, and fried items, as these foods generally elevate blood lipid levels, encourage oxidative stress, and initiate inflammatory reactions, which can hasten kidney deterioration. Moreover, sufficient dietary fiber intake, a low-sodium diet, and adequate hydration are also crucial elements for maintaining optimal kidney performance.
This research exhibited several strengths, including a considerable sample size and a prospective cohort framework. Additionally, we gathered participants’ detailed lifestyle information from the UK Biobank to formulate lifestyle scores. Utilizing Lasso regression and the Random Forest algorithm, we pinpointed pertinent metabolites and assessed their relationships with CKD. Furthermore, we utilized accelerated failure time (AFT) models to examine the factors linked to the speeding up or slowing down of the latency period of chronic kidney disease (CKD). However, several limitations should be acknowledged: Firstly, lifestyle information was gathered at baseline via surveys, physical measurements, and self-reports, lacking insights into potential lifestyle modifications during the follow-up, which may cause estimation inaccuracies for new CKD cases. Secondly, the applicability of our results may be restricted owing to specific study limitations. The research was restricted to the United Kingdom, comprising primarily White participants aged 40–69 years. Dietary and lifestyle variables in this cohort might differ from those in other regions and ethnic groups. Moreover, we did not gather data on CKD occurrence in other age brackets or healthy populations, which could provide further understanding.
