MON-2, a Golgi protein, mediates autophagy-dependent longevity in
            <i>Caenorhabditis elegans</i>

Jung, Yoonji; Artan, Murat; Kim, Nari; Yeom, Jeonghun; Hwang, Ara B.; Jeong, Dae‐Eun; Altintas, Ozlem; Seo, Keunhee; Seo, Mihwa; Lee, Dong-Yeop; Hwang, Wooseon; Lee, Yujin; Sohn, Jooyeon; Kim, Eun Ji E.; Ju, Sungeun; Han, Seong Kyu; Nam, Hyun‐Jun; Ryu, Youngjae; Moon, Dong Jin; Kang, Chanhee; Yoo, Joo‐Yeon; Ha, Chang Man; Hansen, Malene; Kim, Sanguk; Lee, Cheolju; Park, Seung-Yeol; Lee, Seung-Jae

doi:10.1126/sciadv.abj8156

Cited by 14 publications

(17 citation statements)

References 81 publications

(99 reference statements)

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“…Furthermore, several proteases that are normally being elevated during aging were reduced, particularly starting during mid-age in long-lived daf-2(RNAi) animals (Figure 3A, Supplementary Table 9). Consistent with our proteomics, across six different longevity interventions (dietary restriction, metformin, glp-1, daf-2, isp-1, eat-2) and data sets (Depuydt et al, 2013;Espada et al, 2020;Jung et al, 2021;Koyuncu et al, 2021;Pu et al, 2017), we observed an increase of a subset of cuticular collagens (col-) protein levels, collagen-stabilizing and remodeling enzymes (dpy-18, phy-2, bli-, nas-, zmp-) and a decrease of cathepsin (cpl-, cpz-, cpr-) protease levels (Figure 3B, Supplementary Table 9). We thus propose that longevity interventions mobilize compensatory adjustments counteracting age-related ECM changes, especially in older animals, presumably to maintain homeostasis of the ECM proteins.…”

Section: Longevity Interventions Counteract Age-dependent Ecm Composi...supporting

confidence: 84%

Mechanotransduction coordinates extracellular matrix protein homeostasis promoting longevity inC. elegans

Teuscher

Statzer

Goyala

et al. 2022

Preprint

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Although it is postulated that dysfunctional extracellular matrices (ECM) drive aging and disease, how ECM integrity assures longevity is unknown. Here, using proteomics and in-vivo monitoring of fluorescently tagged ECM proteins, we systematically examined the ECM composition during Caenorhabditis elegans aging revealing three distinct collagen dynamics. We show that age-dependent stiffening of inert collagen was slowed by longevity interventions through prolonged replenishing of collagens. In genetic and automated lifespan screens for the regulators that drive this remodeling, we identify hemidesmosome-containing structures that span from the exoskeletal ECM through the hypodermis, basement membrane ECM, to the muscles, coupling mechanical forces to adjust ECM gene expression across tissues. The hemidesmosome tension-induced adaptation is mediated via transcriptional co-activator YAP. Our data reveal a novel mechanism of mechano-coupling and synchronizing of two functionally distinct and spatially distant ECMs that is indispensable for longevity. Thus, besides signaling molecules, mechanotransduction-coordinated ECM remodeling systemically promotes healthy aging.

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Section: Longevity Interventions Counteract Age-dependent Ecm Composi...supporting

confidence: 84%

Mechanotransduction coordinates extracellular matrix protein homeostasis promoting longevity inC. elegans

Teuscher

Statzer

Goyala

et al. 2022

Preprint

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“… 87 Similarly, mammalian MON2 (a Golgi protein) is upregulated in long-lived C. elegans , and MON2 is essential for stimulating autophagic flux by activating the Atg8 orthologue GABARAP/LGG-1 in C. elegans to extend longevity. 89 Starvation, lipid restriction, proteins or special amino acid deletions activate autophagy. 90 – 92 Overactive autophagy in response to fasting is partially regulated by activation of AMPK and SIRT1 activity and inhibition of mTOR activity.…”

Section: Nutrient-associated Molecular Mechanismsmentioning

confidence: 99%

Dietary regulation in health and disease

Gao

et al. 2022

Sig Transduct Target Ther

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Nutriments have been deemed to impact all physiopathologic processes. Recent evidences in molecular medicine and clinical trials have demonstrated that adequate nutrition treatments are the golden criterion for extending healthspan and delaying ageing in various species such as yeast, drosophila, rodent, primate and human. It emerges to develop the precision-nutrition therapeutics to slow age-related biological processes and treat diverse diseases. However, the nutritive advantages frequently diversify among individuals as well as organs and tissues, which brings challenges in this field. In this review, we summarize the different forms of dietary interventions extensively prescribed for healthspan improvement and disease treatment in pre-clinical or clinical. We discuss the nutrient-mediated mechanisms including metabolic regulators, nutritive metabolism pathways, epigenetic mechanisms and circadian clocks. Comparably, we describe diet-responsive effectors by which dietary interventions influence the endocrinic, immunological, microbial and neural states responsible for improving health and preventing multiple diseases in humans. Furthermore, we expatiate diverse patterns of dietotheroapies, including different fasting, calorie-restricted diet, ketogenic diet, high-fibre diet, plants-based diet, protein restriction diet or diet with specific reduction in amino acids or microelements, potentially affecting the health and morbid states. Altogether, we emphasize the profound nutritional therapy, and highlight the crosstalk among explored mechanisms and critical factors to develop individualized therapeutic approaches and predictors.

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“…MON-2 regulates trafficking between endosomes and the Golgi apparatus (Mahajan et al, 2013). Similarly, TBC-3 is also involved in transport between endosomes and Golgi (Kanamori et al, 2008) and is required for isp-1 lifespan (Jung et al, 2021). While MON-2 appears to be promoting longevity by upregulating autophagy, it is unclear how elevated endosomal MON-2 increases autophagy (Artan et al, 2022; Jung et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

“…Among the most well studied mitochondrial mutants in Caenorhabditis elegans are nuo-6 and isp-1 .The nuo-6 gene encodes a subunit of Complex I of the mitochondrial electron transport chain (Yang and Hekimi, 2010), while the isp-1 gene encodes a subunit of the Rieske iron sulfur protein in Complex III of the electron transport chain (Feng et al, 2001). Although a number of studies have identified factors that are important for the long lifespan of these mitochondrial mutants (Baruah et al, 2014; Campos et al, 2021; Harris-Gauthier et al, 2022; Hwang et al, 2014; Jung et al, 2021; Lee et al, 2010; Munkacsy et al, 2016; Senchuk et al, 2018; Walter et al, 2011; Wu et al, 2018; Yee et al, 2014), the mechanism by which mild mitochondrial impairment extends longevity remains incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

Endosomal trafficking protein TBC-2 is required for the longevity of long-lived mitochondrial mutants

Traa¹,

Shields²,

AlOkda³

et al. 2023

Preprint

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Mutations that result in a mild impairment of mitochondrial function can extend longevity. Previous studies have shown that the increase in lifespan is dependent on stress responsive transcription factors, including DAF-16/FOXO, which exhibits increased nuclear localization in long-lived mitochondrial mutants. We recently found that the localization of DAF-16 within the cell is dependent on the endosomal trafficking protein TBC-2. Based on the important role of DAF-16 in both longevity and resistance to stress, we examined the effect of disrupting tbc-2 on lifespan and stress resistance in the long-lived mitochondrial mutants nuo-6 and isp-1 in C. elegans. Loss of tbc-2 markedly reduced the long lifespans of both mitochondrial mutants. Disruption of tbc-2 also decreased resistance to specific exogenous stressors in nuo-6 and isp-1 mutants. In contrast, tbc-2 inhibition had no effect on oxidative stress resistance or lifespan in isp-1 worms when DAF-16 is absent suggesting that the effect of tbc-2 on mitochondrial mutant lifespan may be mediated by mislocalization of DAF-16. However, this result is complicated by the fact that deletion of daf-16 markedly decreases both phenotypes in isp-1 worms. Surprisingly, disruption of tbc-2 did not prevent the upregulation of DAF-16 target genes in the long-lived mitochondrial mutants, suggesting the possibility that the effect of tbc-2 on lifespan and stress resistance in the long-lived mitochondrial mutants is at least partially independent of its effects on DAF-16 localization. Overall, this work demonstrates the importance of endosomal trafficking for the extended longevity and enhanced stress resistance resulting from mild impairment of mitochondrial function.

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MON-2, a Golgi protein, mediates autophagy-dependent longevity in Caenorhabditis elegans

Abstract: MON-2, which mediates Golgi-endosome trafficking, mediates mitochondrial inhibition–induced longevity by enhancing autophagy.

Cited by 14 publications

References 81 publications

Mechanotransduction coordinates extracellular matrix protein homeostasis promoting longevity inC. elegans

Mechanotransduction coordinates extracellular matrix protein homeostasis promoting longevity inC. elegans

Dietary regulation in health and disease

Endosomal trafficking protein TBC-2 is required for the longevity of long-lived mitochondrial mutants

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