A diet of oxidative stress-adapted bacteria improves stress resistance and lifespan inC. elegansvia p38-MAPK DOI Open Access
Ajay Bhat, Rebecca L. Cox,

Brice Graham Hendrickson

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Окт. 6, 2023

Abstract Organisms across taxa are exposed to stresses such as variable temperature, redox imbalance, and xenobiotics. Successfully responding stress restoring homeostasis is crucial for viability of the organism. During aging, ability effectively respond declines, contributing development disease. In many multicellular animals, aging also coincides with changes in microbiome that can contribute disease-states. Because animals their microbiota coexist same broad environment, they each must adapt similar stresses. However, short generation time microbes leads faster evolution, allowing possibility microbial adaptation may influence host physiology. Here we leverage a simplified model involving nematode C. elegans its bacterial diet. Our work highlights how oxidative impacts host’s lifespan response stress. Intriguingly, our findings reveal worms fed bacteria adapted withstand exhibit enhanced resistance an extended lifespan. Through whole genome sequencing, genetic assays, metabolic analysis, this study underscores pivotal role iron-sulfur pathway governing We further find iron stress-evolved boost worm’s through activation mitogen-activated protein kinase (MAPK) pathway. conclusion, provides evidence understanding evolutionary path during could be leveraged slow mitigate age-related decline health.

Язык: Английский

fmo-4 promotes longevity and stress resistance via ER to mitochondria calcium regulation in C. elegans DOI Open Access
Angela M. Tuckowski, Safa Beydoun,

Elizabeth S Kitto

и другие.

Опубликована: Янв. 27, 2025

Flavin-containing monooxygenases (FMOs) are a conserved family of xenobiotic enzymes upregulated in multiple longevity interventions, including nematode and mouse models. Previous work supports that C. elegans fmo-2 promotes longevity, stress resistance, healthspan by rewiring endogenous metabolism. However, there five FMOs mammalian FMOs, it is not known whether promoting health benefits role this gene family. Here, we report expression fmo-4 lifespan extension paraquat resistance downstream both dietary restriction inhibition mTOR. We find overexpression just the hypodermis sufficient for these benefits, significantly modifies transcriptome. By analyzing changes expression, genes related to calcium signaling altered expression. Highlighting importance homeostasis pathway, overexpressing animals sensitive thapsigargin, an ER stressor inhibits flux from cytosol lumen. This calcium/ interaction solidified data showing modulating intracellular with either small molecules or genetics can change and/or interact affect resistance. Further analysis pathway where modulates activating transcription factor-6 ( atf-6 ), whose knockdown induces requires Together, our identify as longevity-promoting actions pathways homeostasis.

Язык: Английский

Процитировано

0
N-formylkynurenine but not kynurenine enters a nucleophile-scavenging branch of the immune-regulatory kynurenine pathway DOI Creative Commons
Yongxin Wang, Euphemia Leung, Petr Tomek

и другие.

Bioorganic Chemistry, Год журнала: 2025, Номер unknown, С. 108219 - 108219

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

0
fmo-4 promotes longevity and stress resistance via ER to mitochondria calcium regulation in C. elegans DOI Creative Commons
Angela M. Tuckowski, Safa Beydoun,

Elizabeth S Kitto

и другие.

eLife, Год журнала: 2025, Номер 13

Опубликована: Фев. 14, 2025

Flavin-containing monooxygenases (FMOs) are a conserved family of xenobiotic enzymes upregulated in multiple longevity interventions, including nematode and mouse models. Previous work supports that C. elegans fmo-2 promotes longevity, stress resistance, healthspan by rewiring endogenous metabolism. However, there five FMOs mammalian FMOs, it is not known whether promoting health benefits role this gene family. Here, we report expression fmo-4 lifespan extension paraquat resistance downstream both dietary restriction inhibition mTOR. We find overexpression just the hypodermis sufficient for these benefits, significantly modifies transcriptome. By analyzing changes expression, genes related to calcium signaling altered expression. Highlighting importance homeostasis pathway, overexpressing animals sensitive thapsigargin, an ER stressor inhibits flux from cytosol lumen. This calcium/ interaction solidified data showing modulating intracellular with either small molecules or genetics can change and/or interact affect resistance. Further analysis pathway where modulates activating transcription factor-6 ( atf-6 ), whose knockdown induces requires Together, our identify as longevity-promoting actions pathways homeostasis.

Язык: Английский

Процитировано

0
The Role of Hypoxia in Longevity DOI Creative Commons
Ayesha Nisar,

Sawar Khan,

Yongzhang Pan

и другие.

Aging and Disease, Год журнала: 2025, Номер unknown, С. 0 - 0

Опубликована: Янв. 1, 2025

Aging is marked by a progressive decrease in physiological function and reserve capacity, which results increased susceptibility to diseases. Understanding the mechanisms of driving aging crucial for extending health span promoting human longevity. Hypoxia, reduced oxygen availability, has emerged as promising area study within research. This review explores recent findings on potential restriction promote healthy extend lifespan. While role hypoxia-inducible factor 1 (HIF-1) cellular responses hypoxia well-established, its impact lifespan remains complex context-dependent. Investigations invertebrate models suggest HIF-1 longevity, while evidence mammalian limited. Hypoxia extends independent dietary (DR), known intervention underlying However, both DR converge common downstream effectors, such forkhead box O (FOXO) flavin-containing monooxygenase (FMOs) modulate Further work required elucidate molecular hypoxia-induced longevity optimize clinical applications. crosstalk between other longevity-associated pathways developing interventions enhance healthspan. Future studies may uncover novel therapeutic strategies populations.

Язык: Английский

Процитировано

0
CELF1 Promotes Post-myocardial Infarction Cardiac Remodeling Via Suppression of FMO2 DOI

Jun Lai,

Likang Li,

Jun Liu

и другие.

Cardiovascular Toxicology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 28, 2025

Язык: Английский

Процитировано

0
The Roles of White Adipose Tissue and Liver NADPH in Dietary Restriction-Induced Longevity DOI Creative Commons

Leah E. Jamerson,

Patrick C. Bradshaw

Antioxidants, Год журнала: 2024, Номер 13(7), С. 820 - 820

Опубликована: Июль 8, 2024

Dietary restriction (DR) protocols frequently employ intermittent fasting. Following a period of fasting, meal consumption increases lipogenic gene expression, including that NADPH-generating enzymes fuel lipogenesis in white adipose tissue (WAT) through the induction transcriptional regulators SREBP-1c and CHREBP. knockout mice, unlike controls, did not show an extended lifespan on DR diet. WAT cytoplasmic NADPH is generated by both malic enzyme 1 (ME1) pentose phosphate pathway (PPP), while liver primarily synthesized folate cycle provided one-carbon units serine catabolism. During daily fasting diet, fatty acids are released from transported to peripheral tissues, where they used for beta-oxidation phospholipid lipid droplet synthesis, monounsaturated (MUFAs) may activate Nrf1 inhibit ferroptosis promote longevity. Decreased PPP stimulated browning protected high-fat high levels macrophages linked obesity. But oscillations [NADPH]/[NADP+] feeding cycles play important role maintaining metabolic plasticity drive Studies measuring malate/pyruvate as proxy [NADPH]/[NADP+], well studies using fluorescent biosensors expressed animal models monitor changes needed during ad libitum diets determine associated with

Язык: Английский

Процитировано

3
A diet of oxidative stress–adapted bacteria improves stress resistance and lifespan in C. elegans via p38-MAPK DOI Creative Commons
Ajay Bhat, Rebecca L. Cox,

Brice Graham Hendrickson

и другие.

Science Advances, Год журнала: 2024, Номер 10(14)

Опубликована: Апрель 3, 2024

Organisms across taxa face stresses including variable temperature, redox imbalance, and xenobiotics. Successfully responding to stress restoring homeostasis are crucial for survival. Aging is associated with a decreased response alterations in the microbiome, which contribute disease development. Animals their microbiota share environment; however, microbes have short generation time can rapidly evolve potentially affect host physiology during stress. Here, we leverage Caenorhabditis elegans its simplified bacterial diet demonstrate how microbial adaptation oxidative affects host’s lifespan response. We find that worms fed stress-evolved bacteria exhibit enhanced resistance an extended lifespan. Through comprehensive genetic metabolic analysis, iron enhances worm via activation of mitogen-activated protein kinase pathway. In conclusion, our study provides evidence understanding stress–mediated adaptations could be used slow aging alleviate age-related health decline.

Язык: Английский

Процитировано

2
Metabolomic and transcriptomic analyses of Fmo5-/- mice reveal roles for flavin-containing monooxygenase 5 (FMO5) in NRF2-mediated oxidative stress response, unfolded protein response, lipid homeostasis, and carbohydrate and one-carbon metabolism DOI Creative Commons
Ian Phillips, Sunil Veeravalli, Sanjay Khadayate

и другие.

PLoS ONE, Год журнала: 2023, Номер 18(6), С. e0286692 - e0286692

Опубликована: Июнь 2, 2023

Flavin-containing monooxygenase 5 (FMO5) is a member of the FMO family proteins, best known for their roles in detoxification foreign chemicals and, more recently, endogenous metabolism. We have previously shown that Fmo5-/- mice display an age-related lean phenotype, with much reduced weight gain from 20 weeks age. The phenotype characterized by decreased fat deposition, lower plasma concentrations glucose, insulin and cholesterol, higher glucose tolerance sensitivity, resistance to diet-induced obesity. In present study we report use metabolomic transcriptomic analyses livers wild-type identify factors underlying insights into function FMO5. Metabolomics was performed Metabolon platform, utilising ultrahigh performance liquid chromatography-tandem mass spectroscopy. Transcriptomics RNA-Seq results analysed DESeq2. Disruption Fmo5 gene has wide-ranging effects on abundance metabolites expression genes liver. Metabolites whose concentration differed between include several saturated monounsaturated fatty acids, complex lipids, amino one-carbon intermediates ADP-ribose. Among most significantly and/or highly differentially expressed are Apoa4, Cd36, Fitm1, Hspa5, Hyou1, Ide, Me1 Mme. reveal FMO5 involved upregulating NRF2-mediated oxidative stress response, unfolded protein response hypoxia cellular stress, indicating role enzyme adaptation metabolic stress. also plays stimulating wide range pathways processes, particularly ones lipid homeostasis, uptake metabolism generation cytosolic NADPH, predict acts NRF2, XBP1, PPARA PPARG regulatory pathways, while inhibiting STAT1 IRF7 pathways.

Язык: Английский

Процитировано

5
Flavin containing monooxygenase 2 regulates renal tubular cell fibrosis and paracrine secretion via SMURF2 in AKI‑CKD transformation DOI Creative Commons
Long-Fei Wang, Hongchu Zha, Jing Huang

и другие.

International Journal of Molecular Medicine, Год журнала: 2023, Номер 52(5)

Опубликована: Окт. 4, 2023

In the follow‑up of hospitalized patients with acute kidney injury (AKI), it has been observed that 15‑30% these progress to develop chronic disease (CKD). Impaired adaptive repair kidneys following AKI is a fundamental pathophysiological mechanism underlying renal fibrosis and progression CKD. Deficient proximal tubular epithelial cells key factor in from However, molecular mechanisms involved regulation fibrotic paracrine secretion by injured remain incompletely understood. Transcriptome analysis an ischemia‑reperfusion (IRI) model were used identify contribution flavin‑containing monooxygenase 2 (FMO2) AKI‑CKD. Lentivirus‑mediated overexpression FMO2 was performed mice. Functional experiments conducted using TGF‑β‑induced cell fibrogenesis pro‑fibrotic secretion. Expression attenuated induced IRI, fibrosis, immune infiltration into kidneys. Overexpression not only effectively blocked TGF but also inhibited aberrant activation factors present fibroblasts. negatively regulated TGF‑β‑mediated SMAD2/3 promoting expression SMAD ubiquitination regulatory (SMURF2) its nuclear translocation. During transition CKD, modulated through SMURF2, thereby affecting outcome disease.

Язык: Английский

Процитировано

4
Flavin‐containing monooxygenase (FMO): Beyond xenobiotics DOI
Ajay Bhat,

Faith R. Carranza,

Angela M. Tuckowski

и другие.

BioEssays, Год журнала: 2024, Номер 46(7)

Опубликована: Май 7, 2024

Flavin-containing monooxygenases (FMOs), traditionally known for detoxifying xenobiotics, are now recognized their involvement in endogenous metabolism. We recently discovered that an isoform of FMO, fmo-2 Caenorhabditis elegans, alters metabolism to impact longevity and stress tolerance. Increased expression C. elegans modifies the flux through key pathway as One Carbon Metabolism (OCM). This modified results a decrease ratio S-adenosyl-methionine (SAM) S-adenosyl-homocysteine (SAH), consequently diminishing methylation capacity. Here we discuss how FMO-2-mediated formate production during tryptophan may serve trigger changing OCM. suggest bridges OCM, altering metabolic away from overexpression. Additionally, highlight these intersect with mTOR AMPK pathways, addition mitochondrial In conclusion, goal this essay is bring attention central role FMO enzymes but lack understanding mechanisms. justify call deeper enzyme's rewiring tryptophan/formate or other yet unidentified substrates. emphasize identification novel drugs microbes induce activity extend lifespan.

Язык: Английский

Процитировано

1