Insights into the action of the pharmaceutical metformin: Targeted inhibition of the gut microbial enzyme agmatinase

Tassoulas, Lambros J.; Wackett, Lawrence P.

doi:10.1016/j.isci.2024.108900

Cited by 3 publications

(2 citation statements)

References 70 publications

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“…Large portion of agmatine in mammals is supplemented from diets and gut microbiota and long-term (5 years) supplementation studies (Gilad and Gilad, 2014) have demonstrated its safety in the examined doses. Beneficial effects on the host's lifespan through microbiome-derived agmatine induced by metformin treatment have been previously reported (Pryor et al, 2019;Tassoulas and Wackett, 2024). Indeed, agmatine can augment metformin's therapeutic effects.…”

Section: Discussionmentioning

confidence: 91%

Rapalink-1 reveals novel mTOR-dependent genes and an agmatinergic axis-based metabolic feedback regulating mTOR activity and lifespan

Kumar,

Rallis

2024

Preprint

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AbstractmTOR is a conserved pro-ageing pathway with characterised inhibitors such as rapamycin, rapalogues and torins. A third-generation inhibitor, rapalink-1, has been developed, however, its effects on organismal gene expression and lifespan have not been evaluated. Here, we demonstrate that rapalink-1 affects fission yeast spatial and temporal growth and prolongs chronological lifespan. Endosome and vesicle-mediated transport and homeostasis processes related to autophagy and Pik3, the orthologue of human PI3K, render cells resistant to rapalink-1. Our study reveals mTOR-regulated genes with unknown roles in ageing including all fission yeast agmatinases, the enzymes responsible for processing agmatine to putrescine and urea. We identify sensitive and resistant mutants to agmatine and putrescine and show that all fission yeast agmatinase enzymes are required for normal lifespan. Genetic interactome assays for the agmatinaseagm1and further cell and molecular analyses, demonstrate that impairing the agmatinergic branch of arginine catabolism results in mTOR activity levels that are beneficial for growth but detrimental for chronological ageing. Our study reveals metabolic feedback circuits with possible implications to other systems, including human cells.

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Section: Discussionmentioning

confidence: 91%

Rapalink-1 reveals novel mTOR-dependent genes and an agmatinergic axis-based metabolic feedback regulating mTOR activity and lifespan

Kumar,

Rallis

2024

Preprint

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“…The anti-diabetic drug metformin provides many benefits in human health, including anti-hyperglycemic and anti-aging effects, at least in part by altering the gut microbiome [ 46 ]. Long-term use of metformin in diabetic patients has been linked with vitamin B12 deficiency and peripheral neuropathy [ 47 ].…”

Section: Insights Into Host–microbiome Interactions In C El...mentioning

confidence: 99%

Caenorhabditis elegans as a Convenient Animal Model for Microbiome Studies

Wu,

Davis,

Saudagar

et al. 2024

IJMS

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Microbes constitute the most prevalent life form on Earth, yet their remarkable diversity remains mostly unrecognized. Microbial diversity in vertebrate models presents a significant challenge for investigating host–microbiome interactions. The model organism Caenorhabditis elegans has many advantages for delineating the effects of host genetics on microbial composition. In the wild, the C. elegans gut contains various microbial species, while in the laboratory it is usually a host for a single bacterial species. There is a potential host–microbe interaction between microbial metabolites, drugs, and C. elegans phenotypes. This mini-review aims to summarize the current understanding regarding the microbiome in C. elegans. Examples using C. elegans to study host–microbe–metabolite interactions are discussed.

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Biochemical and genomic evidence for converging metabolic routes of metformin and biguanide breakdown in environmental Pseudomonads

Wissbroecker,

Zmuda,

Karumanchi

et al. 2024

Journal of Biological Chemistry

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Insights into the action of the pharmaceutical metformin: Targeted inhibition of the gut microbial enzyme agmatinase

Cited by 3 publications

References 70 publications

Rapalink-1 reveals novel mTOR-dependent genes and an agmatinergic axis-based metabolic feedback regulating mTOR activity and lifespan

Rapalink-1 reveals novel mTOR-dependent genes and an agmatinergic axis-based metabolic feedback regulating mTOR activity and lifespan

Caenorhabditis elegans as a Convenient Animal Model for Microbiome Studies

Biochemical and genomic evidence for converging metabolic routes of metformin and biguanide breakdown in environmental Pseudomonads

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