Sestrin is a key regulator of stem cell function and lifespan in response to dietary amino acids

Lu, Jiongming; Temp, Ulrike; Müller-Hartmann, Andrea; Eßer, Jacqueline; Grönke, Sebastian; Partridge, Linda

doi:10.1038/s43587-020-00001-7

Cited by 30 publications

(23 citation statements)

References 79 publications

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“…. Indeed, AA sensing regulates stem cell proliferation, gut homeostasis, lifespan, and mTORC1 in flies via Sestrin, which encodes a homolog of the mammalian Sestrin proteins which regulate BCAA sensing by mTORC1 (Chantranupong et al, 2014;Lu et al, 2021;Saxton et al, 2016). Therefore, we were surprised that Low AA and Low Ile feeding did not alter the phosphorylation of S6, a downstream readout of mTORC1, and 4E-BP1, an mTORC1 substrate, in the liver (Figure 3A).…”

Section: Reduction Of Dietary Ile Is Necessary For the Beneficial Metabolic Effects Of An Lp Dietmentioning

confidence: 98%

The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine

et al. 2021

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Section: Reduction Of Dietary Ile Is Necessary For the Beneficial Metabolic Effects Of An Lp Dietmentioning

confidence: 98%

The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine

et al. 2021

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“…Tao et al demonstrated that SESN3 protected high-fat-fed mice against insulin resistance through the mTORC2/Akt pathway [ 13 ]. Therefore, evidence suggests that Sesns are essential in maintaining metabolic homeostasis and protecting against hypernutrition [ 13 , 22 , 58 – 61 ].…”

Section: Biological Functions Of Sesns In Human Pathophysiological Processesmentioning

confidence: 99%

“…Restriction of specific essential amino acids plays a key role, but the molecular and cellular mechanisms are still elusive [ 60 ]. Recent studies show that Sesns may be the link between dietary amino acids, intestinal stem cell function, gut health, and lifespan by regulating the mTOR pathway and autophagy, which could provide another clue for human disease prevention [ 61 ].…”

Section: Future Directions: Sesns As Biomarkers and Therapeutic Targets Of Diseasesmentioning

confidence: 99%

The functions and roles of sestrins in regulating human diseases

Chen

Huang

et al. 2022

Cell Mol Biol Lett

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Sestrins (Sesns), highly conserved stress-inducible metabolic proteins, are known to protect organisms against various noxious stimuli including DNA damage, oxidative stress, starvation, endoplasmic reticulum (ER) stress, and hypoxia. Sesns regulate metabolism mainly through activation of the key energy sensor AMP-dependent protein kinase (AMPK) and inhibition of mammalian target of rapamycin complex 1 (mTORC1). Sesns also play pivotal roles in autophagy activation and apoptosis inhibition in normal cells, while conversely promoting apoptosis in cancer cells. The functions of Sesns in diseases such as metabolic disorders, neurodegenerative diseases, cardiovascular diseases, and cancer have been broadly investigated in the past decades. However, there is a limited number of reviews that have summarized the functions of Sesns in the pathophysiological processes of human diseases, especially musculoskeletal system diseases. One aim of this review is to discuss the biological functions of Sesns in the pathophysiological process and phenotype of diseases. More significantly, we include some new evidence about the musculoskeletal system. Another purpose is to explore whether Sesns could be potential biomarkers or targets in the future diagnostic and therapeutic process.

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“…Sestrin 2 (SESN2) is an intracellular leucine sensor that negatively regulates the TORC1 signaling pathway. This gene was out of the scope of DR-relatedness until a recent work highlighted its role as a novel molecular link that mediates the effects of dietary amino acid restriction on TORC1 activity in stem cells of the fly gut, thereby maintaining gut health and ensuring longevity [66]. Hence, although the DR-probability of this gene was relatively low in the {PathDIP, CAT} model, it was the highest in the {GO terms, BRF} model; and the averaged DR-related prediction of this gene is supported by recent evidence.…”

Section: Dr-related Candidate Genesmentioning

confidence: 99%

Machine learning-based predictions of dietary restriction associations across ageing-related genes

et al. 2022

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Background Dietary restriction (DR) is the most studied pro-longevity intervention; however, a complete understanding of its underlying mechanisms remains elusive, and new research directions may emerge from the identification of novel DR-related genes and DR-related genetic features. Results This work used a Machine Learning (ML) approach to classify ageing-related genes as DR-related or NotDR-related using 9 different types of predictive features: PathDIP pathways, two types of features based on KEGG pathways, two types of Protein–Protein Interactions (PPI) features, Gene Ontology (GO) terms, Genotype Tissue Expression (GTEx) expression features, GeneFriends co-expression features and protein sequence descriptors. Our findings suggested that features biased towards curated knowledge (i.e. GO terms and biological pathways), had the greatest predictive power, while unbiased features (mainly gene expression and co-expression data) have the least predictive power. Moreover, a combination of all the feature types diminished the predictive power compared to predictions based on curated knowledge. Feature importance analysis on the two most predictive classifiers mostly corroborated existing knowledge and supported recent findings linking DR to the Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) signalling pathway and G protein-coupled receptors (GPCR). We then used the two strongest combinations of feature type and ML algorithm to predict DR-relatedness among ageing-related genes currently lacking DR-related annotations in the data, resulting in a set of promising candidate DR-related genes (GOT2, GOT1, TSC1, CTH, GCLM, IRS2 and SESN2) whose predicted DR-relatedness remain to be validated in future wet-lab experiments. Conclusions This work demonstrated the strong potential of ML-based techniques to identify DR-associated features as our findings are consistent with literature and recent discoveries. Although the inference of new DR-related mechanistic findings based solely on GO terms and biological pathways was limited due to their knowledge-driven nature, the predictive power of these two features types remained useful as it allowed inferring new promising candidate DR-related genes.

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Sestrin is a key regulator of stem cell function and lifespan in response to dietary amino acids

Cited by 30 publications

References 79 publications

The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine

The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine

The functions and roles of sestrins in regulating human diseases

Machine learning-based predictions of dietary restriction associations across ageing-related genes

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