Spatial and single-cell profiling of the metabolome, transcriptome and epigenome of the aging mouse liver

Nature Aging, Journal Year: 2023, Volume and Issue: 3(11), P. 1430 - 1445

Published: Nov. 9, 2023

Abstract Tissues within an organism and even cell types a tissue can age with different velocities. However, it is unclear whether cells of one type experience aging trajectories depending on their spatial location. Here, we used transcriptomics in combination single-cell ATAC-seq RNA-seq, lipidomics functional assays to address how the male murine liver are affected by age-related changes microenvironment. Integration datasets revealed zonation-specific metabolic states, epigenome transcriptome. The changed zonation-dependent manner functionally, periportal hepatocytes were characterized decreased mitochondrial fitness, whereas pericentral accumulated large lipid droplets. Together, provide evidence that changing microenvironments exert strong influences resident shape epigenetic, phenotypic outputs.

Language: Английский

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Modulation of ER-mitochondria tethering complex VAPB-PTPIP51: Novel therapeutic targets for aging-associated diseases

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 98, P. 102320 - 102320

Published: May 6, 2024

Aging is a gradual and irreversible natural process. With aging, the body experiences functional decline, effects amplify vulnerability to range of age-related diseases, including neurodegenerative, cardiovascular, metabolic diseases. Within aging process, morphology function mitochondria endoplasmic reticulum (ER) undergo alterations, particularly in structure connecting these organelles known as mitochondria-associated membranes (MAMs). MAMs serve vital intracellular signaling hubs, facilitating communication between ER when regulating various cellular events, calcium homeostasis, lipid metabolism, mitochondrial function, apoptosis. The formation partly dependent on interaction vesicle-associated membrane protein-associated protein-B (VAPB) protein tyrosine phosphatase-interacting protein-51 (PTPIP51). Accumulating evidence has begun elucidate pivotal role VAPB-PTPIP51 tether initiation progression In this study, we delineate intricate multifunctional discuss its profound implications aging-associated Moreover, provide comprehensive overview potential therapeutic interventions pharmacological agents targeting VAPB-PTPIP51-mediated MAMs, thereby offering glimmer hope mitigating processes treating disorders.

Language: Английский

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The Gut Microbial Regulation of Epigenetic Modification from a Metabolic Perspective

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(13), P. 7175 - 7175

Published: June 29, 2024

Obesity is a global health challenge that has received increasing attention in contemporary research. The gut microbiota been implicated the development of obesity, primarily through its involvement regulating various host metabolic processes. Recent research suggests epigenetic modifications may serve as crucial pathways which and metabolites contribute to pathogenesis obesity other disorders. Hence, understanding interplay between mechanisms for elucidating impact on host. This review focuses relationship with several obesity-related pathogenic mechanisms, including energy dysregulation, inflammation, maternal inheritance. These findings could novel therapeutic targets probiotics, prebiotics, fecal transplantation tools treating disruptions. It also aid developing strategies modulate microbiota, thereby characteristics obesity.

Language: Английский

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Regulation of cardiovascular health and disease by visceral adipose tissue‐derived metabolic hormones

The Journal of Physiology, Journal Year: 2022, Volume and Issue: 601(11), P. 2099 - 2120

Published: June 6, 2022

Abstract Visceral adipose tissue (VAT) is a metabolic organ known to regulate fat mass, and glucose nutrient homeostasis. VAT an active endocrine gland that synthesizes secretes numerous bioactive mediators called ‘adipocytokines/adipokines’ into systemic circulation. These adipocytokines act on organs of importance like the liver skeletal muscle. Multiple preclinical in vitro studies showed strong evidence roles regulation disorders diabetes, obesity insulin resistance. Adipocytokines, such as adiponectin omentin, are anti‐inflammatory have been shown prevent atherogenesis by increasing nitric oxide (NO) production endothelium, suppressing endothelium‐derived inflammation decreasing foam cell formation. By inhibiting differentiation vascular smooth muscle cells (VSMC) osteoblasts, omentin calcification. On other hand, leptin resistin induce endothelial dysfunction leads vasoconstriction. promoting VSMC migration proliferation, extracellular matrix degradation inflammatory polarization macrophages, increase risk atherosclerotic plaque vulnerability rupture. Additionally, plasma concentrations these alter ageing, rendering older humans vulnerable cardiovascular disease. The disturbances normal physiological secreted under pathological conditions impede functions various affect health. adipokines could be used for both diagnostic therapeutic purposes image

Language: Английский

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DO‐SRS imaging of diet regulated metabolic activities in Drosophila during aging processes

Aging Cell, Journal Year: 2022, Volume and Issue: 21(4)

Published: March 7, 2022

Lipid metabolism plays crucial roles during aging processes, but how it is regulated by diets and interplays with still remain unclear. We proposed a new optical imaging platform integrating heavy water (D2 O) probing stimulated Raman scattering (DO-SRS) microscopy, for the first time, to directly visualize quantify lipid different insulin signaling pathway in Drosophila fat body aging. found that calorie restriction, low protein diet, (moderately) high sucrose enhanced turnover flies at all ages, while fructose glucose only promoted aged flies. The measured enhancements under diverse were due mechanisms. High diet shortened lifespan other extended lifespan. Downregulating turnover, which likely related increase, upregulating decreased would shorten Our study offers approach spatiotemporal alterations of situ, better understanding interconnections between metabolism, diets,

Language: Английский

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PAHSAs reduce cellular senescence and protect pancreatic beta cells from metabolic stress through regulation of Mdm2/p53

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(47)

Published: Nov. 14, 2022

Senescence in pancreatic beta cells plays a major role cell dysfunction, which leads to impaired glucose homeostasis and diabetes. Therefore, prevention of senescence could reduce the risk Treatment nonobese diabetic (NOD) mice, model type 1 autoimmune diabetes (T1D), with palmitic acid hydroxy stearic acids (PAHSAs), novel class endogenous lipids antidiabetic antiinflammatory effects, delays onset reduces incidence T1D from 82% vehicle treatment 35% PAHSAs. Here, we show that mechanism by PAHSAs protect islets NOD mice is directly preventing reversing initial steps metabolic stress–induced senescence. In vitro increased Mdm2 expression, decreases stability p53, key inducer senescence-related genes. addition, enhanced expression protective genes, such as those regulating DNA repair glutathione metabolism promoting autophagy. We demonstrate translational relevance showing prevent reverse early stages metabolically stressed human same mechanism. Thus, for dramatic effect reducing decreasing cellular senescence; may have similar benefit humans.

Language: Английский

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Integrative perspective of the healthy aging process considering the metabolome, cardiac autonomic modulation and cardiorespiratory fitness evaluated in age groups

Scientific Reports, Journal Year: 2022, Volume and Issue: 12(1)

Published: Dec. 9, 2022

Abstract The aging process causes changes at all organic levels. Although metabolism, cardiac autonomic modulation (CAM), and cardiorespiratory fitness (CRF) are widely studied as a function of age, they mainly in isolation, thus making it difficult to perceive their concomitant variations. This study aimed investigate the integrated that occur metabolome, CAM, CRF throughout apparently healthy individuals. subjects (n = 118) were divided into five groups according age (20–29, 30–39, 40–49, 50–59, 60–70 years old) underwent blood collection, assessment, cardiopulmonary exercise test for metabolomics analysis using mass spectrometry nuclear magnetic resonance, analysis, by peak oxygen consumption respectively. Tukey’s post hoc effect size with confidence interval used variables significant one-way ANOVA ( P < 0.01). main oldest group, where CRF, valine, leucine, isoleucine, 3-hydroxyisobutyrate, CAM reduced hippuric acid increased. results suggest after sixty consequence impairments, but some metabolic profile may be favorable mitigate deleterious effects.

Language: Английский

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Lipid and glucose metabolism in senescence

Frontiers in Nutrition, Journal Year: 2023, Volume and Issue: 10

Published: Aug. 23, 2023

Senescence is an inevitable biological process. Disturbances in glucose and lipid metabolism are essential features of cellular senescence. Given the important roles these types metabolism, we review evidence for how key metabolic enzymes influence senescence senescence-related secretory phenotypes, autophagy, apoptosis, insulin signaling pathways, environmental factors modulate homeostasis. We also discuss alterations abnormal diseases anti-cancer therapies that target through interventions. Our work offers insights developing pharmacological strategies to combat cancer.

Language: Английский

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Bioorthogonal Stimulated Raman Scattering Imaging Uncovers Lipid Metabolic Dynamics in Drosophila Brain During Aging

GEN Biotechnology, Journal Year: 2023, Volume and Issue: 2(3), P. 247 - 261

Published: June 1, 2023

Studies have shown that brain lipid metabolism is associated with biological aging and influenced by dietary genetic manipulations; however, the underlying mechanisms are elusive. High-resolution imaging techniques propose a novel potent approach to understanding metabolic dynamics in situ. Applying deuterium water (D2O) probing stimulated Raman scattering (DO-SRS) microscopy, we revealed activity Drosophila decreased sex-dependent manner. Female flies showed an earlier occurrence of turnover decrease than males. Dietary restriction (DR) downregulation insulin/IGF-1 signaling (IIS) pathway, two scenarios for lifespan extension, led significant enhancements old flies. Combining SRS deuterated bioorthogonal probes (deuterated glucose acetate), discovered that, under DR treatment IIS shifted use acetate as major carbon source synthesis. For first time, our study directly visualizes quantifies spatiotemporal alterations at single organelle (lipid droplet) level. Our not only demonstrates new studying situ but also illuminates interconnection aging, dietary, manipulations on regulation.

Language: Английский

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The Influence of Antioxidants on Oxidative Stress-Induced Vascular Aging in Obesity

Antioxidants, Journal Year: 2023, Volume and Issue: 12(6), P. 1295 - 1295

Published: June 17, 2023

Obesity is a worldwide trend that growing in incidence very fast. Adipose tissue dysfunction caused by obesity associated with the generation of oxidative stress. Obesity-induced stress and inflammation play key role pathogenesis vascular diseases. Vascular aging one main mechanisms. The aim this study to review effect antioxidants on obesity. In order achieve aim, paper designed obesity-caused adipose remodeling, generated high levels stress, effects obesity, redox balance, aging. It seems diseases obese individuals are complex networks pathological develop proper therapeutic tool, first, there need for better understanding interactions between Based these interactions, suggests different lines strategies include change lifestyle prevent control remodelling, oxidant-antioxidant suppression, against Some support strategies, making them appropriate conditions such as stress-induced individuals.

Language: Английский

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