scholarly journals Thyme and Oregano Terpenoids Activate Autophagy and Protect Against Hepatic Steatosis

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 336-336
Author(s):  
Gabriele Civiletto ◽  
Guillaume Eric Jacot ◽  
Federico Sizzano ◽  
Kamila Muller ◽  
Aurélie Hermant ◽  
...  
Keyword(s):  
Caloric Restriction ◽  
Metabolic Diseases ◽  
Screening Strategy ◽  
Fluorescent Reporter ◽  
Calcium Dependent ◽  
Hormetic Effect ◽  
Age Related ◽  
Mouse Tissues ◽  
Living Organisms

Abstract Caloric restriction has been shown to reduce chronic illness in aging and increase life expectancy in most living organisms including mammals. Autophagy, a ubiquitous catabolic pathway of cellular quality control, is a key mechanism mediating the benefits of caloric restriction. In addition, mutations in genes involved in autophagy have been associated with the early onset of age-related diseases such as neurodegeneration, highlighting autophagy as a potential therapeutic target. Here, we aimed to discover autophagy inducers from a library of edible molecules for potential use in food applications. To this end, we developed a novel in vivo high-content screening strategy using fluorescent reporter zebrafish that monitor autophagy flux in skeletal muscle. We identify the thyme and oregano constituent thymol as a novel potent autophagy inducer in zebrafish, human cells and mouse tissues. Mechanistically, thymol triggers an hormetic effect on mitochondria in synergism with a calcium-dependent autophagy response which, in turn, leads to mobilization of intracellular lipid stores. We tested the effects of chronic thymol supplementation in mice fed a high-fat diet and showed that thymol mobilizes fatty acids, reduces liver triglycerides and improves markers of liver damage. In sum, we validate the use of zebrafish screening as a discovery model for autophagy-based therapeutics and demonstrate that thymol is an autophagy inducer with potential for the prevention of chronic metabolic diseases and other age-related conditions.

scholarly journals Treating Senescence like Cancer: Novel Perspectives in Senotherapy of Chronic Diseases

2020 ◽  
Vol 21 (21) ◽  
pp. 7984
Author(s):  
Alessia Mongelli ◽  
Sandra Atlante ◽  
Veronica Barbi ◽  
Tiziana Bachetti ◽  
Fabio Martelli ◽  
...  
Keyword(s):  
Chronic Diseases ◽  
Cell Senescence ◽  
Biological Processes ◽  
Social Relevance ◽  
Chemical Agents ◽  
Age Related ◽  
Living Organisms ◽  
Specific Pathway

The WHO estimated around 41 million deaths worldwide each year for age-related non-communicable chronic diseases. Hence, developing strategies to control the accumulation of cell senescence in living organisms and the overall aging process is an urgently needed problem of social relevance. During aging, many biological processes are altered, which globally induce the dysfunction of the whole organism. Cell senescence is one of the causes of this modification. Nowadays, several drugs approved for anticancer therapy have been repurposed to treat senescence, and others are under scrutiny in vitro and in vivo to establish their senomorphic or senolytic properties. In some cases, this research led to a significant increase in cell survival or to a prolonged lifespan in animal models, at least. Senomorphics can act to interfere with a specific pathway in order to restore the appropriate cellular function, preserve viability, and to prolong the lifespan. On the other hand, senolytics induce apoptosis in senescent cells allowing the remaining non–senescent population to preserve or restore tissue function. A large number of research articles and reviews recently addressed this topic. Herein, we would like to focus attention on those chemical agents with senomorphic or senolytic properties that perspectively, according to literature, suggest a potential application as senotherapeutics for chronic diseases.

scholarly journals Caloric restriction confers persistent anti-oxidative, pro-angiogenic, and anti-inflammatory effects and promotes anti-aging miRNA expression profile in cerebromicrovascular endothelial cells of aged rats

2014 ◽  
Vol 307 (3) ◽  
pp. H292-H306 ◽  
Author(s):  
Anna Csiszar ◽  
Tripti Gautam ◽  
Danuta Sosnowska ◽  
Stefano Tarantini ◽  
Eszter Banki ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Caloric Restriction ◽  
Mirna Expression ◽  
Transcriptional Activity ◽  
Protective Effects ◽  
Cellular Mechanisms ◽  
Cerebrovascular Function ◽  
Age Related ◽  
Anti Inflammatory

In rodents, moderate caloric restriction (CR) without malnutrition exerts significant cerebrovascular protective effects, improving cortical microvascular density and endothelium-dependent vasodilation, but the underlying cellular mechanisms remain elusive. To elucidate the persisting effects of CR on cerebromicrovascular endothelial cells (CMVECs), primary CMVECs were isolated from young (3 mo old) and aged (24 mo old) ad libitum-fed and aged CR F344xBN rats. We found an age-related increase in cellular and mitochondrial oxidative stress, which is prevented by CR. Expression and transcriptional activity of Nrf2 are both significantly reduced in aged CMVECs, whereas CR prevents age-related Nrf2 dysfunction. Expression of miR-144 was upregulated in aged CMVECs, and overexpression of miR-144 significantly decreased expression of Nrf2 in cells derived from both young animals and aged CR rats. Overexpression of a miR-144 antagomir in aged CMVECs significantly decreases expression of miR-144 and upregulates Nrf2. We found that CR prevents age-related impairment of angiogenic processes, including cell proliferation, adhesion to collagen, and formation of capillary-like structures and inhibits apoptosis in CMVECs. CR also exerts significant anti-inflammatory effects, preventing age-related increases in the transcriptional activity of NF-κB and age-associated pro-inflammatory shift in the endothelial secretome. Characterization of CR-induced changes in miRNA expression suggests that they likely affect several critical functions in endothelial cell homeostasis. The predicted regulatory effects of CR-related differentially expressed miRNAs in aged CMVECs are consistent with the anti-aging endothelial effects of CR observed in vivo. Collectively, we find that CR confers persisting anti-oxidative, pro-angiogenic, and anti-inflammatory cellular effects, preserving a youthful phenotype in rat cerebromicrovascular endothelial cells, suggesting that through these effects CR may improve cerebrovascular function and prevent vascular cognitive impairment.

scholarly journals Senescent Cell-Secreted Netrin-1 Modulates Aging-Related Disorders by Recruiting Sympathetic Fibers

2020 ◽  
Vol 12 ◽  
Author(s):  
Ai Qing Yu ◽  
Jie Wang ◽  
Xiao Jia Zhou ◽  
Ke Yu Chen ◽  
You De Cao ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Molecular Mechanisms ◽  
Human Colon ◽  
Senescent Cell ◽  
Aged Mouse ◽  
Age Related ◽  
Mouse Tissues ◽  
6 Hydroxydopamine

Cellular senescence is implicated in several lines of aging-related disorders. However, the potential molecular mechanisms by which cellular senescence modulates age-related pathologies remain largely unexplored. Herein, we report that the density of sympathetic fibers (SFs) is significantly elevated in naturally aged mouse tissues and human colon adenoma tissues compared to the SFs densities in the corresponding young mouse tissues and human non-lesion colon tissues. A dorsal root ganglion (DRG)-human diploid fibroblast coculture assay revealed that senescent cells promote the outgrowth of SFs, indicating that the senescent cells induce recruitment of SFs in vitro. Additionally, subcutaneous transplantation of 2BS fibroblasts in nude mice shows that transplanted senescent 2BS fibroblasts promote SFs infiltration. Intra-articular senolytic molecular injection can reduce SFs density and inhibit SFs infiltration caused by senescent cells in osteoarthritis (OA), suggesting senescent cells promote the infiltration of SFs in vivo in aged tissues. Notably, the elevated level of SFs contributes to impaired cognitive function in naturally aged mice, which can be reversed by treatment with propranolol hydrochloride, a non-selective β receptor blocker that inhibits sympathetic nerve activity (SNA) by blocking non-selective β receptors. Additionally, 6-hydroxydopamine (6-OHDA)-induced sympathectomy improved hepatic sympathetic overactivity mediated hepatic steatosis in high fat diet (HFD)-fed APOE knockout mice (APOE−/− mice) by reducing hepatic SNA. Taken together, this study concludes that senescent cell-secreted netrin-1 mediated SFs outgrowth and infiltration, which contributes to aging-related disorders, suggesting that clearing senescent cells or inhibiting SNA is a promising therapeutic strategy for improving sympathetic nervous system (SNS) hyperactivity-induced aging-related pathologies.

scholarly journals Immunosenescence in some but not all immune components in a free-living vertebrate, the tree swallow

2007 ◽  
Vol 274 (1612) ◽  
pp. 951-957 ◽  
Author(s):  
Maria G Palacios ◽  
Joan E Cunnick ◽  
David W Winkler ◽  
Carol M Vleck
Keyword(s):  
T Cell ◽  
Immune Function ◽  
Tree Swallow ◽  
Future Research ◽  
Cell Mediated Immunity ◽  
Free Living ◽  
Age Related ◽  
Living Organisms

A wide diversity of free-living organisms show increases in mortality rates and/or decreases in reproductive success with advancing age. However, the physiological mechanisms underlying these demographic patterns of senescence are poorly understood. Immunosenescence, the age-related deterioration of immune function, is well documented in humans and laboratory models, and often leads to increased morbidity and mortality due to disease. However, we know very little about immunosenescence in free-living organisms. Here, we studied immunosenescence in a free-living population of tree swallows, Tachycineta bicolor , assessing three components of the immune system and using both in vivo and in vitro immunological tests. Immune function in tree swallow females showed a complex pattern with age; acquired T-cell mediated immunity declined with age, but neither acquired nor innate humoral immunity did. In vitro lymphocyte proliferation stimulated by T-cell mitogens decreased with age, suggesting that reduced T-cell function might be one mechanism underlying the immunosenescence pattern of in vivo cell-mediated response recently described for this same population. Our results provide the most thorough description of immunosenescence patterns and mechanisms in a free-living vertebrate population to date. Future research should focus on the ecological implications of immunosenescence and the potential causes of variation in patterns among species.

scholarly journals Modulation of Heat Shock Factor 1 Activity through Silencing of Ser303/Ser307 Phosphorylation Supports a Metabolic Program Leading to Age-Related Obesity and Insulin Resistance

2018 ◽  
Vol 38 (18) ◽  
Author(s):  
Xiongjie Jin ◽  
Aijun Qiao ◽  
Demetrius Moskophidis ◽  
Nahid F. Mivechi
Keyword(s):  
Insulin Resistance ◽  
Heat Shock ◽  
Metabolic Diseases ◽  
Cellular Stress ◽  
Heat Shock Factor ◽  
Model Systems ◽  
Central Feature ◽  
Heat Shock Factor 1 ◽  
Age Related

ABSTRACT Activation of the adaptive response to cellular stress orchestrated by heat shock factor 1 (HSF1), which is an evolutionarily conserved transcriptional regulator of chaperone response and cellular bioenergetics in diverse model systems, is a central feature of organismal defense from environmental and cellular stress. HSF1 activity, induced by proteostatic, metabolic, and growth factor signals, is regulated by posttranscriptional modifications, yet the mechanisms that regulate HSF1 and particularly the functional significance of these modifications in modulating its biological activity in vivo remain unknown. HSF1 phosphorylation at both Ser303 (S303) and Ser307 (S307) has been shown to repress HSF1 transcriptional activity under normal physiological growth conditions. To determine the biological relevance of these HSF1 phosphorylation events, we generated a knock-in mouse model in which S303 and S307 were replaced with alanine (HSF1303A/307A). Our results confirmed that loss of phosphorylation in HSF1303A/307A cells and tissues increases protein stability but also markedly sensitizes HSF1 activation under normal and heat- or nutrient-induced stress conditions. Interestingly, the enhanced HSF1 activation in HSF1303A/307A mice activates a supportive metabolic program that aggravates the development of age-dependent obesity, fatty liver diseases, and insulin resistance. Thus, these findings highlight the importance of a posttranslational mechanism (through phosphorylation at S303 and S307 sites) of regulation of the HSF1-mediated transcriptional program that moderates the severity of nutrient-induced metabolic diseases.

scholarly journals Phosphatidylcholine Extends Lifespan via DAF-16 and Reduces Amyloid-Beta-Induced Toxicity in Caenorhabditis elegans

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
So-Hyeon Kim ◽  
Bo-Kyoung Kim ◽  
Suhyeon Park ◽  
Sang-Kyu Park
Keyword(s):  
Oxidative Stress ◽  
Amyloid Beta ◽  
Dietary Intervention ◽  
Disease Model ◽  
Cellular Membrane ◽  
Cellular Mechanisms ◽  
Hormetic Effect ◽  
Age Related ◽  
Significant Difference

Phosphatidylcholine is one of the major phospholipids comprising cellular membrane and is known to have several health-promoting activities, including the improvement of brain function and liver repair. In this paper, we examine the in vivo effect of dietary supplementation with phosphatidylcholine on the response to environmental stressors and aging in C. elegans. Treatment with phosphatidylcholine significantly increased the survival of worms under oxidative stress conditions. However, there was no significant difference in response to stresses caused by heat shock or ultraviolet irradiation. Oxidative stress is believed to be one of the major causal factors of aging. Then, we examined the effect of phosphatidylcholine on lifespan and age-related physiological changes. Phosphatidylcholine showed a lifespan-extending effect and a reduction in fertility, possibly as a tradeoff for long lifespan. Age-related decline of motility was also significantly delayed by supplementation with phosphatidylcholine. Interestingly, the expressions of well-known longevity-assuring genes, hsp-16.2 and sod-3, were significantly upregulated by dietary intervention with phosphatidylcholine. DAF-16, a transcription factor modulating stress response genes, was accumulated in the nucleus by phosphatidylcholine treatment. Increase of the ROS level with phosphatidylcholine suggests that the antioxidant and lifespan-extending effects are due to the hormetic effect of phosphatidylcholine. Phosphatidylcholine also showed a protective effect against amyloid beta-induced toxicity in Alzheimer’s disease model animals. Experiments with long-lived mutants revealed that the lifespan-extending effect of phosphatidylcholine specifically overlapped with that of reduced insulin/IGF-1-like signaling and required DAF-16. These findings showed the antioxidant and antiaging activities of phosphatidylcholine for the first time in vivo. Further studies focusing on the identification of underlying cellular mechanisms involved in the antiaging effect will increase the possibility of using phosphatidylcholine for the development of antiaging therapeutics.

scholarly journals Caloric Restriction Impedes Age-Related Decline of Mitochondrial Function and Neuronal Activity

2014 ◽  
Vol 34 (9) ◽  
pp. 1440-1443 ◽  
Author(s):  
Ai-Ling Lin ◽  
Daniel Coman ◽  
Lihong Jiang ◽  
Douglas L Rothman ◽  
Fahmeed Hyder
Keyword(s):  
Caloric Restriction ◽  
Neuronal Activity ◽  
Mitochondrial Function ◽  
Healthy Aging ◽  
Resonance Spectroscopy ◽  
Young Control ◽  
Brain Physiology ◽  
Age Related ◽  
Effects Of Aging

Caloric restriction (CR) prolongs lifespan and retards many detrimental effects of aging, but its effect on brain mitochondrial function and neuronal activity—especially in healthy aging—remains unexplored. Here we measured rates of neuronal glucose oxidation and glutamate–glutamine neurotransmitter cycling in young control, old control (i.e., healthy aging), and old CR rats using in vivo nuclear magnetic resonance spectroscopy. We found that, compared with the young control, neuronal energy production and neurotransmission rates were significantly reduced in healthy aging, but were preserved in old CR rats. The results suggest that CR mitigated the age-related deceleration of brain physiology.

scholarly journals A Self-Immobilizing NIR Probe for Non-invasive Imaging of Senescence

2020 ◽  
Author(s):  
Jun Liu ◽  
Xiaowei Ma ◽  
Chao Cui ◽  
Ying Wang ◽  
Philip R. Deenik ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Near Infrared ◽  
Cellular Stress Response ◽  
Quinone Methide ◽  
Fluorescence Signal ◽  
Drug Induced ◽  
Non Invasive ◽  
Age Related ◽  
Living Organisms

AbstractCellular senescence, a process that arrests the cell cycle, is a cellular stress response to various stimuli and is implicated in aging and age-related diseases. However, the understanding of senescence in living organisms is insufficient, largely due to the scarcity of sensitive tools for the detection of cellular senescence in vivo. Herein, we describe the development of a self-immobilizing near-infrared (NIR) probe that can be activated by senescence-associated β- Galactosidase (SA-β-Gal), a widely accepted senescence marker. The NIR fluorophore is turned on in the presence of SA-β-Gal, and the self-immobilizing group, based on quinone methide chemistry, retains the fluorescence signal to the site of activation. This strategy significantly improves the sensitivity of the probe from the one we developed before. We demonstrate the non-invasive imaging of drug-induced senescence in mice models.

In vivo Experiments of Natural Products Protection of Antagonistic Effects of Lead on Iron

2018 ◽  
Vol 68 (12) ◽  
pp. 2747-2751
Author(s):  
Marioara Nicula ◽  
Nicolae Pacala ◽  
Lavinia Stef ◽  
Ioan Pet ◽  
Dorel Dronca ◽  
...  
Keyword(s):  
Aquatic Environment ◽  
Iron Homeostasis ◽  
Iron Concentration ◽  
Antagonistic Effect ◽  
Tissue Samples ◽  
Antagonistic Effects ◽  
In Vivo Experiments ◽  
Living Organisms ◽  
Toxic Potential

Living organisms take nutrients from the environment, and together with them, substances with toxic potential � such as heavy metals. Lead is one common metal pollutant especially in aquatic environment, from where the fish can be intoxicated very easily. Bioavailability, distribution, toxic action, synergistic and antagonistic effects are characteristics which can alter the fish health. Our experimental study followed the effects of lead overload in water on iron distribution, in different tissues sample Carassius gibelio Bloch fish. We performed the experiment in four different fish groups: control C; lead � Pb (administration of lead in water 0.075mg/mL of water, as Pb(NO3)2 x � H2O); lead (the same dose) and 2% of freeze-dry garlic incorporated into fishes� food � Pb+garlic; lead (the same dose) and 2% chlorella incorporated into fishes� food � Pb+chlorella, for 21 consecutive days. The iron concentration was analysed with AAS (Atomic Absorption Spectroscopy) from gills, muscle, skin (and scales), intestine, liver, heart, brain, ovary, testicles, and kidney. The obtained data presented a significantly decrease of iron content in all tested tissue samples that demonstrated, alteration of iron homeostasis, explained by a strong antagonistic effect of lead on iron. Our experiment showed that biologic active principles from garlic and chlorella act like natural protectors, and potentiate the iron deficiency even in the case of lead overload in aquatic environment, for fish.

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